Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006457 protein folding	IBA GO_REF:0000033	ACCEPT	Summary: DNAJB1 is a class II J-domain co-chaperone that promotes protein folding through the HSP70 chaperone machinery. Rauch and Gestwicki (PMID:24318877) showed that combinations of J proteins including DnaJB1 with NEFs and HSP70 produce potent chaperone activities in luciferase refolding assays. Hageman et al. (PMID:21231916) showed that DNAJB1 supports luciferase refolding when paired with HSP70, classifying it as a foldase-type co-chaperone. The IBA annotation for protein folding is well supported by phylogenetic inference and experimental data. Reason: Protein folding is the core biological process of DNAJB1. As a class II J-domain co-chaperone, DNAJB1 delivers substrates to HSP70 and stimulates the ATPase-dependent folding cycle (PMID:24318877, PMID:21231916). This IBA annotation is consistent with extensive experimental evidence and phylogenetic conservation. Supporting Evidence: PMID:24318877 we combined the Hsp70-NEF pairs with cochaperones of the J protein family (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The activity of the combinations in ATPase and luciferase refolding assays were dependent on the identity and stoichiometry of both the J protein and NEF PMID:21231916 chaperones that supported luciferase refolding were poor suppressors of polyQ aggregation.
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: DNAJB1 is primarily a cytosolic protein. Hageman et al. (PMID:21231916) stated that most HSP70/HSPA and HSP40/DNAJ proteins are localized in the cytosol. UniProt confirms cytoplasmic localization. The IBA annotation for cytosol is well supported. Reason: Cytosol is the primary localization of DNAJB1 under normal conditions, consistent with its role as a cytosolic co-chaperone for HSP70. Phylogenetic inference and direct experimental evidence (immunofluorescence, PMID:21231916) support this. Supporting Evidence: PMID:21231916 Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding genes and most of the corresponding proteins are localized in the cytosol.
GO:0000122 negative regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: DNAJB1 negatively regulates HSF1-driven transcription during the attenuation phase of the heat shock response. Shi et al. (PMID:9499401) demonstrated that Hsp70 and the cochaperone Hdj1 (DNAJB1) interact directly with the transactivation domain of HSF1 and repress heat shock gene transcription. The IBA annotation is well supported. Reason: While experimentally validated (PMID:9499401), negative regulation of transcription is not a core molecular function of DNAJB1 but rather a downstream consequence of its co-chaperone activity in the HSP70 complex. DNAJB1 represses HSF1 transcription as part of the heat shock attenuation mechanism, which is a secondary regulatory role. The IBA annotation is phylogenetically sound. Supporting Evidence: PMID:9499401 the molecular chaperone Hsp70 and the cochaperone Hdj1 interact directly with the transactivation domain of HSF1 and repress heat shock gene transcription.
GO:0003714 transcription corepressor activity	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Shi et al. (PMID:9499401) showed that overexpression of Hdj1 (DNAJB1) represses the transcriptional activity of HSF1, including a transfected GAL4-HSF1 activation domain fusion protein. This demonstrates transcription corepressor activity. The IBA annotation is phylogenetically consistent. Reason: Transcription corepressor activity is a real but non-core function of DNAJB1. It acts as a corepressor specifically in the context of HSF1-mediated heat shock gene transcription, working together with HSP70 to repress the HSF1 transactivation domain (PMID:9499401). This is a secondary regulatory role dependent on its primary co-chaperone activity, not a general transcription corepressor function. Supporting Evidence: PMID:9499401 Overexpression of either chaperone represses the transcriptional activity of a transfected GAL4-HSF1 activation domain fusion protein and endogenous HSF1.
GO:0030544 Hsp70 protein binding	IBA GO_REF:0000033	ACCEPT	Summary: DNAJB1 is a J-domain co-chaperone that physically binds HSP70 family members through its J-domain. UniProt records interactions with HSP70/HSPA1A (PMID:14503850) and this is a defining feature of all J-domain proteins. The IBA annotation accurately reflects the core molecular function of DNAJB1. Reason: HSP70 binding via the J-domain is the core molecular function of DNAJB1 as a J-domain co-chaperone. This is the defining feature of the DnaJ family and is essential for DNAJB1's ability to stimulate HSP70 ATPase activity and deliver substrates. Phylogenetically well-conserved and experimentally validated.
GO:0051082 unfolded protein binding	IBA GO_REF:0000033	MODIFY	Summary: GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962). DNAJB1 is a class II J-domain protein that functions as a foldase-type co-chaperone for HSP70, not as an independent holdase. Hageman et al. (PMID:21231916) showed that DNAJB1 promotes efficient luciferase refolding when paired with HSP70, placing it in the foldase category. UniProt describes DNAJB1 as stimulating ATP hydrolysis and the folding of unfolded proteins mediated by HSPA1A/B. The correct replacement term is GO:0044183 (protein folding chaperone), which accurately describes DNAJB1's role in binding to proteins to assist the protein folding process as part of the HSP70 chaperone machinery. Reason: GO:0051082 is scheduled for obsoletion. The obsolescence notice (go-ontology#30962) specifies that annotations should be migrated to either holdase chaperone activity or GO:0044183 (protein folding chaperone, i.e. foldase). DNAJB1 is definitively a foldase-type co-chaperone, not a holdase. Hageman et al. (PMID:21231916) demonstrated that chaperones supporting luciferase refolding (foldase activity) were poor suppressors of polyQ aggregation (holdase activity), and vice versa. DNAJB1 promotes refolding when paired with HSP70, classifying it as a foldase. This IBA annotation by phylogenetic inference correctly identified the general chaperone activity of DNAJB1, but the term needs updating to GO:0044183 to reflect the foldase function and the obsolescence of GO:0051082. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:21231916 Overexpressed chaperones that suppressed polyQ aggregation were found not to be able to stimulate luciferase refolding. Inversely, chaperones that supported luciferase refolding were poor suppressors of polyQ aggregation.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: DNAJB1 translocates from the cytoplasm to the nucleus upon heat shock. UniProt subcellular location annotation confirms nuclear localization under stress conditions, supported by Hattori et al. (PubMed:1586970). This IEA annotation from UniProtKB subcellular location vocabulary mapping is consistent with known biology. Reason: Nuclear localization of DNAJB1 upon heat shock is well-documented. UniProt states that DNAJB1 translocates rapidly from the cytoplasm to the nucleus upon heat shock. The IEA mapping from UniProt subcellular location is appropriate.
GO:0005730 nucleolus	IEA GO_REF:0000044	ACCEPT	Summary: DNAJB1 translocates to the nucleolus upon heat shock. UniProt subcellular location confirms nucleolar localization under stress, supported by Hattori et al. (PubMed:1586970). The IEA annotation is consistent with known stress-induced translocation behavior. Reason: Nucleolar localization of DNAJB1 upon heat shock is documented in UniProt based on Hattori et al. The IEA mapping from UniProt subcellular location vocabulary is appropriate. DNAJB1 translocates to the nucleolus under heat shock stress.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: DNAJB1 is primarily cytoplasmic under normal conditions. UniProt subcellular location lists cytoplasm as a primary location. This is broader than the cytosol annotation but acceptable as an IEA annotation. Reason: Cytoplasmic localization of DNAJB1 is well-established. While the cytosol annotation is more specific, cytoplasm is a valid broader term from the UniProt mapping. Both are correct.
GO:0006457 protein folding	IEA GO_REF:0000120	ACCEPT	Summary: Protein folding is a core process for DNAJB1 as a J-domain co-chaperone. This IEA annotation from combined automated methods is consistent with the IBA annotation and experimental evidence. Reason: Redundant with the IBA annotation for the same term, but the IEA is independently valid. Protein folding is a core function of DNAJB1 through its HSP70 co-chaperone activity.
GO:0006986 response to unfolded protein	IEA GO_REF:0000117	ACCEPT	Summary: DNAJB1 is a heat shock-inducible co-chaperone that participates in the cellular response to unfolded proteins. As a J-domain protein that delivers substrates to HSP70, it is involved in the response to unfolded protein. This IEA annotation from ARBA machine learning is reasonable. Reason: DNAJB1 is indeed involved in the response to unfolded protein as a heat shock-inducible J-domain co-chaperone. While the term is broad, it is appropriate for an IEA annotation. It is consistent with the TAS annotation for the same term (PMID:8975727).
GO:0051082 unfolded protein binding	IEA GO_REF:0000002	MODIFY	Summary: GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962). This IEA annotation was inferred from the InterPro domain IPR008971 (HSP40/DnaJ peptide-binding domain) mapping to GO:0051082. While the DnaJ peptide-binding domain does indeed interact with substrates, the function of DNAJB1 is best described as protein folding chaperone activity (GO:0044183), as DNAJB1 acts as a foldase-type co-chaperone for HSP70. DNAJB1 does not independently hold unfolded proteins; it delivers substrates to HSP70 and stimulates the ATPase-dependent folding cycle. Reason: GO:0051082 is scheduled for obsoletion (go-ontology#30962). This IEA annotation derives from the InterPro domain mapping (IPR008971, HSP40/DnaJ peptide-binding domain). The InterPro2GO mapping will need to be updated when GO:0051082 is obsoleted. For DNAJB1 specifically, the correct replacement is GO:0044183 (protein folding chaperone), since DNAJB1 is a foldase-type J-domain protein that promotes protein refolding in concert with HSP70 (PMID:21231916). Proposed replacements: protein folding chaperone Supporting Evidence: PMID:21231916 Overexpressed chaperones that suppressed polyQ aggregation were found not to be able to stimulate luciferase refolding. Inversely, chaperones that supported luciferase refolding were poor suppressors of polyQ aggregation.
GO:0051087 protein-folding chaperone binding	IEA GO_REF:0000117	ACCEPT	Summary: DNAJB1 binds HSP70 family members (protein-folding chaperones) through its J-domain. This IEA annotation from ARBA machine learning is consistent with the known interaction between DNAJB1 and HSP70 chaperones (PMID:9499401, PMID:24318877). Reason: DNAJB1 is a co-chaperone that physically binds protein-folding chaperones (HSP70 family members). This IEA annotation is appropriate and consistent with the more specific Hsp70 protein binding annotation.
GO:0005515 protein binding	IPI PMID:17024176 A novel HSF1-mediated death pathway that is suppressed by he...	REMOVE	Summary: Hayashida et al. (PMID:17024176) studied a novel HSF1-mediated death pathway suppressed by heat shock proteins. The paper reports that Hsps bound directly to the N-terminal pleckstrin-homology like domain of Tdag51 and suppressed death activity. DNAJB1 binding was detected in this context. Reason: Protein binding is uninformative as a GO annotation. The interaction described in PMID:17024176 between HSPs and Tdag51 is tangential to DNAJB1 core function. More specific terms such as Hsp70 protein binding or protein-folding chaperone binding already capture the meaningful interactions of DNAJB1. Supporting Evidence: PMID:17024176 Hsps bound directly to the N-terminal pleckstrin-homology like (PHL) domain of Tdag51, and suppressed death activity of the C-terminal proline/glutamine/histidine-rich domain.
GO:0005515 protein binding	IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi...	REMOVE	Summary: PMID:21044950 is a genome-wide YFP fluorescence complementation screen for telomere signaling regulators. This is a large-scale screen and the protein binding annotation is uninformative. Reason: Protein binding is uninformative. This large-scale screen result does not provide specific functional insight into DNAJB1's molecular function. More informative MF terms such as Hsp70 protein binding already exist.
GO:0005515 protein binding	IPI PMID:21163940 Interactome mapping suggests new mechanistic details underly...	REMOVE	Summary: PMID:21163940 is an interactome mapping study related to Alzheimer's disease. The protein binding annotation from this large-scale study is uninformative. Reason: Protein binding is uninformative. Large-scale interactome mapping does not provide specific functional insight for DNAJB1 curation.
GO:0005515 protein binding	IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc...	REMOVE	Summary: PMID:25036637 describes a quantitative chaperone interaction network. While relevant to understanding DNAJB1 as a chaperone, the protein binding annotation is uninformative. The interactions are better captured by Hsp70 protein binding and protein-folding chaperone binding terms. Reason: Protein binding is uninformative. The chaperone interaction network data is better captured by the more specific Hsp70 protein binding and protein-folding chaperone binding annotations already present.
GO:0005515 protein binding	IPI PMID:27173435 An organelle-specific protein landscape identifies novel dis...	REMOVE	Summary: PMID:27173435 describes an organelle-specific protein landscape. The protein binding annotation is uninformative for DNAJB1 curation. Reason: Protein binding is uninformative. Large-scale proteomics does not provide specific functional insight for DNAJB1.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	REMOVE	Summary: PMID:28514442 describes architecture of the human interactome. The protein binding annotation from this large-scale interactome study is uninformative. Reason: Protein binding is uninformative. Large-scale interactome mapping does not provide specific functional insight for DNAJB1.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: PMID:32296183 is a reference map of the human binary protein interactome. The protein binding annotation is uninformative. Reason: Protein binding is uninformative. Large-scale interactome mapping does not provide specific functional insight for DNAJB1.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	REMOVE	Summary: PMID:32814053 is an interactome mapping study of neurodegenerative disease proteins. The protein binding annotation is uninformative. Reason: Protein binding is uninformative. Interactome mapping for neurodegenerative disease does not provide specific functional insight for DNAJB1.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: PMID:33961781 describes dual proteome-scale networks of the human interactome. The protein binding annotation is uninformative. Reason: Protein binding is uninformative. Large-scale interactome mapping does not provide specific functional insight for DNAJB1.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	REMOVE	Summary: PMID:35271311 (OpenCell) is an endogenous tagging study for cellular organization cartography. The protein binding annotation is uninformative. Reason: Protein binding is uninformative. Large-scale cellular organization studies do not provide specific functional insight for DNAJB1.
GO:0005515 protein binding	IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c...	REMOVE	Summary: PMID:36931259 describes a chaperone-like role for 14-3-3 proteins. The protein binding annotation is uninformative. Reason: Protein binding is uninformative. The interaction with 14-3-3 proteins may be interesting but the generic protein binding term does not capture any specific functional relationship.
GO:0014069 postsynaptic density	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: This IEA annotation was transferred from an ortholog by Ensembl Compara. DNAJB1 is a ubiquitous co-chaperone without specific synaptic function. While chaperones may be present at the postsynaptic density for proteostasis, there is no evidence that postsynaptic density is a primary or functionally significant localization for DNAJB1. Reason: DNAJB1 is a ubiquitously expressed co-chaperone. Its presence at the postsynaptic density likely reflects general proteostasis rather than a specific synaptic function. This ortholog transfer may over-annotate a non-specific localization.
GO:0030900 forebrain development	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: This IEA annotation was transferred from an ortholog by Ensembl Compara. DNAJB1 is a ubiquitous co-chaperone, and there is no specific evidence linking it to forebrain development as a core function. Reason: DNAJB1 is ubiquitously expressed and functions as a general co-chaperone for HSP70. Forebrain development likely reflects pleiotropic developmental consequences of general protein folding activity rather than a specific role for DNAJB1 in forebrain development. This is likely an over-annotation from ortholog transfer.
GO:0043025 neuronal cell body	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: This IEA annotation was transferred from an ortholog by Ensembl Compara. DNAJB1 is a ubiquitous cytosolic co-chaperone. Its presence in neuronal cell bodies reflects general cytoplasmic/cytosolic localization rather than specific neuronal enrichment. Reason: DNAJB1 is ubiquitously expressed. Neuronal cell body localization likely reflects general cytosolic presence rather than specific neuronal targeting. This is an over-annotation from ortholog transfer.
GO:0043197 dendritic spine	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: This IEA annotation was transferred from an ortholog by Ensembl Compara. DNAJB1 is a ubiquitous co-chaperone without known specific dendritic spine function. Reason: DNAJB1 is a ubiquitous co-chaperone. Dendritic spine localization from ortholog transfer likely represents general proteostasis rather than specific synaptic function. This is an over-annotation.
GO:0044183 protein folding chaperone	IEA GO_REF:0000107	ACCEPT	Summary: DNAJB1 functions as a protein folding chaperone (foldase-type) as part of the HSP70 machinery. Hageman et al. (PMID:21231916) demonstrated that DNAJB1 supports luciferase refolding when paired with HSP70. This IEA annotation from Ensembl Compara ortholog transfer is accurate. Reason: Protein folding chaperone is the correct MF term for DNAJB1 as a foldase-type J-domain co-chaperone. This is consistent with the proposed replacement for the obsolete GO:0051082 annotations and accurately reflects DNAJB1 core function. Supporting Evidence: PMID:21231916 Overexpressed chaperones that suppressed polyQ aggregation were found not to be able to stimulate luciferase refolding. Inversely, chaperones that supported luciferase refolding were poor suppressors of polyQ aggregation.
GO:0061827 sperm head	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: This IEA annotation was transferred from an ortholog by Ensembl Compara. While PMID:21630459 (HDA) independently identifies DNAJB1 in the sperm nucleus proteome, sperm head localization is likely a reflection of general chaperone presence rather than specific function. Reason: Sperm head localization is not a core annotation for DNAJB1 but is supported by independent proteomic evidence (PMID:21630459, HDA for nucleus). Chaperones are expected to be present in spermatozoa for proteostasis. Keep as non-core.
GO:0098794 postsynapse	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: This IEA annotation was transferred from an ortholog by Ensembl Compara. DNAJB1 is a ubiquitous co-chaperone; postsynaptic localization is not specific to DNAJB1. Reason: DNAJB1 is ubiquitously expressed. Postsynapse localization from ortholog transfer likely represents general proteostasis presence rather than specific synaptic function. Over-annotation.
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: This IEA annotation was transferred from an ortholog by Ensembl Compara. DNAJB1 is a ubiquitous co-chaperone without known specific glutamatergic synapse function. Reason: DNAJB1 is ubiquitously expressed. Glutamatergic synapse localization from ortholog transfer likely represents general proteostasis rather than specific synaptic function. Over-annotation.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: DNAJB1 is detected in the nucleoplasm by HPA immunofluorescence (GO_REF:0000052). This is consistent with the known translocation of DNAJB1 to the nucleus upon heat shock (UniProt) and its role in HSF1 regulation in the nucleus (PMID:9499401). Reason: Nucleoplasm localization is consistent with DNAJB1's known nuclear translocation under stress and its role in repressing HSF1 transcriptional activity in the nucleus. HPA immunofluorescence data provides direct evidence.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: DNAJB1 is detected in the cytosol by HPA immunofluorescence (GO_REF:0000052). Consistent with its primary cytosolic localization and role as a cytosolic co-chaperone for HSP70. Reason: Cytosol is the primary localization of DNAJB1 under normal conditions. HPA immunofluorescence confirms this well-established localization.
GO:1900034 regulation of cellular response to heat	TAS Reactome:R-HSA-3371453	ACCEPT	Summary: Reactome R-HSA-3371453 models the regulation of HSF1-mediated heat shock response. DNAJB1 participates in this pathway by repressing HSF1 transcriptional activity together with HSP70 during the attenuation phase (PMID:9499401). Reason: DNAJB1 is a key regulator of the cellular response to heat. It participates in the attenuation of the HSF1-mediated heat shock response by binding HSF1 with HSP70 and repressing transcription (PMID:9499401, Reactome:R-HSA-5082384). This is a well- supported annotation.
GO:0001671 ATPase activator activity	IDA PMID:23921388 Identification and characterization of a novel human methylt...	ACCEPT	Summary: Jakobsson et al. (PMID:23921388) characterized METTL21A methyltransferase and its effects on HSP70. The paper mentions that J-proteins stimulate intrinsic ATPase activity of HSP70s, consistent with DNAJB1 function. However, this paper primarily studies METTL21A, not DNAJB1 directly. Reason: ATPase activator activity is a core molecular function of DNAJB1. As a J-domain co-chaperone, DNAJB1 stimulates the intrinsic ATPase activity of HSP70 family members. While PMID:23921388 focuses on METTL21A, DNAJB1 ATPase activation is extensively documented (PMID:24318877, Reactome:R-HSA-5251959). Multiple independent lines of evidence support this annotation. Supporting Evidence: PMID:23921388 Hsp70 proteins constitute an evolutionarily conserved protein family of ATP-dependent molecular chaperones involved in a wide range of biological processes.
GO:1903334 positive regulation of protein folding	IDA PMID:23921388 Identification and characterization of a novel human methylt...	ACCEPT	Summary: Jakobsson et al. (PMID:23921388) studied methylation effects on HSP70 chaperone function. DNAJB1 positively regulates protein folding by stimulating HSP70 ATPase activity and promoting the HSP70 folding cycle. This is consistent with DNAJB1's well-established foldase co-chaperone role. Reason: Positive regulation of protein folding accurately describes DNAJB1's role as a co-chaperone that stimulates HSP70-mediated folding. This is a core function.
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:9499401 Molecular chaperones as HSF1-specific transcriptional repres...	KEEP AS NON CORE	Summary: Shi et al. (PMID:9499401) directly demonstrated that Hdj1 (DNAJB1) interacts with the transactivation domain of HSF1 and represses heat shock gene transcription. Overexpression of DNAJB1 represses HSF1-driven transcription. Reason: Directly demonstrated by Shi et al. (PMID:9499401) using overexpression of Hdj1 repressing GAL4-HSF1 activation domain fusion and endogenous HSF1. While experimentally valid, this transcriptional repression is specific to the heat shock attenuation context and is a secondary consequence of co-chaperone activity, not a core function. Supporting Evidence: PMID:9499401 Overexpression of either chaperone represses the transcriptional activity of a transfected GAL4-HSF1 activation domain fusion protein and endogenous HSF1.
GO:0034605 cellular response to heat	IDA PMID:9499401 Molecular chaperones as HSF1-specific transcriptional repres...	ACCEPT	Summary: Shi et al. (PMID:9499401) demonstrated that DNAJB1 (Hdj1) participates in the cellular response to heat by interacting with HSF1 during the attenuation phase of the heat shock response. The heat shock response involves DNAJB1 acting with HSP70 to repress HSF1 transcriptional activity. Reason: DNAJB1 is heat shock-inducible and plays a direct role in the cellular response to heat by participating in the attenuation of HSF1-mediated transcription (PMID:9499401). This is well-supported by direct experimental evidence. Supporting Evidence: PMID:9499401 the molecular chaperone Hsp70 and the cochaperone Hdj1 interact directly with the transactivation domain of HSF1 and repress heat shock gene transcription.
GO:0140416 transcription regulator inhibitor activity	IDA PMID:9499401 Molecular chaperones as HSF1-specific transcriptional repres...	KEEP AS NON CORE	Summary: Shi et al. (PMID:9499401) showed that DNAJB1 (Hdj1) directly inhibits HSF1 transcriptional activity by binding to the HSF1 transactivation domain. This constitutes transcription regulator inhibitor activity. Reason: DNAJB1 inhibits HSF1 transcriptional activity during heat shock attenuation (PMID:9499401). While the annotation is accurate, this is not a core molecular function of DNAJB1 but rather a specialized regulatory activity in the HSF1 heat shock response pathway. Its primary role is as a co-chaperone for HSP70. Supporting Evidence: PMID:9499401 the molecular chaperone Hsp70 and the cochaperone Hdj1 interact directly with the transactivation domain of HSF1 and repress heat shock gene transcription.
GO:0001671 ATPase activator activity	TAS Reactome:R-HSA-5251955	ACCEPT	Summary: Reactome R-HSA-5251955 models HSP40s activating intrinsic ATPase activity of HSP70s in the nucleoplasm. DNAJB1 translocates to the nucleus under heat shock and activates HSP70 ATPase activity there. Reason: ATPase activator activity is a core molecular function of DNAJB1. The Reactome annotation for nucleoplasmic ATPase activation is consistent with DNAJB1's known nuclear translocation under heat shock and its ability to stimulate HSP70 ATPase.
GO:0001671 ATPase activator activity	TAS Reactome:R-HSA-5251959	ACCEPT	Summary: Reactome R-HSA-5251959 models HSP40s activating intrinsic ATPase activity of HSP70s in the cytosol. DNAJB1 is explicitly listed as one of the HSP40s that modulates intrinsic ATPase activity of HSP70s. Reason: ATPase activator activity in the cytosol is a core function of DNAJB1. The Reactome pathway explicitly lists DNAJB1 as an HSP40 that activates HSP70 ATPase activity.
GO:0045296 cadherin binding	HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by...	MARK AS OVER ANNOTATED	Summary: PMID:25468996 describes an E-cadherin interactome study using quantitative proteomics. DNAJB1 was identified in the cadherin interactome by high-throughput proteomics. This is likely a non-specific interaction due to DNAJB1's general chaperone activity. Reason: Cadherin binding is not a known or expected function of DNAJB1. As a general co-chaperone, DNAJB1 may associate with many cellular protein complexes for proteostasis without specific binding activity. The HDA evidence from a proteomics screen is not sufficient to establish specific cadherin binding as a function.
GO:0051087 protein-folding chaperone binding	IPI PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	ACCEPT	Summary: Hageman et al. (PMID:21231916) systematically assessed functional differences among HSP70/HSPA and HSP40/DNAJ family members. DNAJB1 was shown to interact with and modulate HSP70 chaperone activity, directly demonstrating protein-folding chaperone binding. Reason: DNAJB1 binds HSP70 chaperones through its J-domain, which is central to its function. PMID:21231916 provides direct evidence of functional DNAJB1-HSP70 interaction in luciferase refolding and polyQ aggregation assays. Supporting Evidence: PMID:21231916 Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding genes and most of the corresponding proteins are localized in the cytosol. To test for possible functional differences and/or substrate specificity, we assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment.
GO:0001671 ATPase activator activity	IDA PMID:24318877 Binding of human nucleotide exchange factors to heat shock p...	ACCEPT	Summary: Rauch and Gestwicki (PMID:24318877) combined Hsp70-NEF pairs with J proteins including DnaJB1 and measured ATPase and luciferase refolding activities. DNAJB1 was directly shown to stimulate HSP70 ATPase activity in these in vitro assays. Reason: ATPase activator activity is a core molecular function of DNAJB1. PMID:24318877 provides direct biochemical evidence of DNAJB1 stimulating HSP70 ATPase activity in vitro. Supporting Evidence: PMID:24318877 we combined the Hsp70-NEF pairs with cochaperones of the J protein family (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The activity of the combinations in ATPase and luciferase refolding assays were dependent on the identity and stoichiometry of both the J protein and NEF
GO:0003714 transcription corepressor activity	IDA PMID:9499401 Molecular chaperones as HSF1-specific transcriptional repres...	KEEP AS NON CORE	Summary: Shi et al. (PMID:9499401) demonstrated that Hdj1 (DNAJB1) represses HSF1 transcriptional activity. Overexpression of DNAJB1 represses both GAL4-HSF1 fusion and endogenous HSF1, functioning as a transcription corepressor in the heat shock response context. Reason: The IDA evidence from PMID:9499401 directly demonstrates corepressor activity on HSF1. This is a duplicate of the IBA annotation for the same term, both supported by the same mechanism. Keep as non-core since transcription corepression is secondary to the primary co-chaperone function. Supporting Evidence: PMID:9499401 Overexpression of either chaperone represses the transcriptional activity of a transfected GAL4-HSF1 activation domain fusion protein and endogenous HSF1.
GO:0005515 protein binding	IPI PMID:9499401 Molecular chaperones as HSF1-specific transcriptional repres...	REMOVE	Summary: Shi et al. (PMID:9499401) showed that Hdj1 (DNAJB1) interacts directly with the transactivation domain of HSF1. This interaction is real but better described by more specific terms (transcription regulator inhibitor activity, protein-folding chaperone binding). Reason: Protein binding is uninformative. The specific interaction with HSF1 described in PMID:9499401 is already captured by the transcription regulator inhibitor activity and transcription corepressor activity annotations. The generic protein binding term adds no additional information.
GO:0005515 protein binding	IPI PMID:27120771 Polyhydramnios, Transient Antenatal Bartter's Syndrome, and ...	REMOVE	Summary: PMID:27120771 concerns MAGED2 mutations and Bartter's syndrome. The paper mentions interaction with a cytoplasmic heat-shock protein but DNAJB1 is not the focus. This protein binding annotation is tangential to DNAJB1 function. Reason: Protein binding is uninformative. PMID:27120771 is primarily about MAGED2 and Bartter's syndrome. Any interaction with DNAJB1 described here is tangential and the generic protein binding term adds no useful information about DNAJB1 function.
GO:0005737 cytoplasm	IDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by...	ACCEPT	Summary: PMID:25468996 is an E-cadherin interactome study. DNAJB1 being detected in the cytoplasm is consistent with its known primary cytoplasmic localization. However, the IDA evidence code from a proteomics study is appropriate. Reason: Cytoplasmic localization of DNAJB1 is well-established and consistent with UniProt subcellular location data. Acceptable as independent confirmation.
GO:0001671 ATPase activator activity	IDA PMID:20060297 Chaperone-assisted selective autophagy is essential for musc...	ACCEPT	Summary: Arndt et al. (PMID:20060297) described chaperone-assisted selective autophagy (CASA) for muscle maintenance. The paper focuses on BAG-3 coordinating Hsc70 and HspB8 during degradation of damaged Z disk components. DNAJB1 ATPase activator activity may be referenced in the context of the HSP70 chaperone cycle but this paper primarily studies the BAG3/CASA pathway. Reason: ATPase activator activity is a core function of DNAJB1. While PMID:20060297 focuses on CASA, DNAJB1's role in activating HSP70 ATPase is well-established across multiple independent studies (PMID:24318877, PMID:23921388, Reactome). The annotation is valid regardless of the specific reference context. Supporting Evidence: PMID:20060297 Stv and its mammalian ortholog BAG-3 coordinate the activity of Hsc70 and the small heat shock protein HspB8 during disposal that is initiated by the chaperone-associated ubiquitin ligase CHIP and the autophagic ubiquitin adaptor p62.
GO:0030544 Hsp70 protein binding	IPI PMID:23921388 Identification and characterization of a novel human methylt...	ACCEPT	Summary: Jakobsson et al. (PMID:23921388) studied METTL21A methyltransferase effects on HSP70. The study demonstrates DNAJB1 interaction with HSP70 family members in the context of methylation modulation of chaperone function. HSP70 binding is a core interaction for DNAJB1. Reason: Hsp70 protein binding is a core molecular function of DNAJB1 as a J-domain co-chaperone. The J-domain of DNAJB1 directly binds HSP70 to stimulate ATPase activity. This annotation is well-supported by multiple studies. Supporting Evidence: PMID:23921388 Hsp70 proteins constitute an evolutionarily conserved protein family of ATP-dependent molecular chaperones involved in a wide range of biological processes.
GO:0051117 ATPase binding	IPI PMID:23921388 Identification and characterization of a novel human methylt...	ACCEPT	Summary: DNAJB1 binds to the ATPase domain of HSP70 through its J-domain. Jakobsson et al. (PMID:23921388) provide context for this interaction in the study of METTL21A methylation effects on HSP70 function. ATPase binding is consistent with DNAJB1's mechanism of action. Reason: ATPase binding accurately describes DNAJB1's interaction with the ATPase domain of HSP70 via its J-domain. This is central to DNAJB1's mechanism of stimulating HSP70 ATPase activity.
GO:0005829 cytosol	TAS Reactome:R-HSA-5690250	ACCEPT	Summary: Reactome R-HSA-5690250 describes phosphorylation of DNAJB1 by MAPKAPK5 in the cytosol. Cytosolic localization of DNAJB1 is well-established and this Reactome annotation is consistent. Reason: Cytosol is the primary localization of DNAJB1. The Reactome pathway for MAPKAPK5 phosphorylation of DNAJB1 correctly places this event in the cytosol.
GO:0005515 protein binding	IPI PMID:23921388 Identification and characterization of a novel human methylt...	REMOVE	Summary: PMID:23921388 studies METTL21A methyltransferase and its effects on HSP70. The protein binding annotation is uninformative when more specific terms (Hsp70 protein binding, ATPase binding) are already present. Reason: Protein binding is uninformative. The specific interactions described are already captured by Hsp70 protein binding and ATPase binding annotations from the same publication.
GO:0005829 cytosol	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	ACCEPT	Summary: Hageman et al. (PMID:21231916) noted that most HSP70/HSPA and HSP40/DNAJ proteins are localized in the cytosol. This directly supports cytosolic localization of DNAJB1. Reason: Cytosolic localization is directly stated in PMID:21231916. This is consistent with other evidence for DNAJB1 as a primarily cytosolic co-chaperone. Supporting Evidence: PMID:21231916 Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding genes and most of the corresponding proteins are localized in the cytosol.
GO:0051082 unfolded protein binding	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	MODIFY	Summary: GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962). This IDA annotation from Hageman et al. (PMID:21231916) demonstrated that DNAJB1 interacts with unfolded/denatured substrates in the context of the HSP70 chaperone machinery. The study assessed effects of overexpression of HSP70/HSPA and HSP40/DNAJ family members on refolding of heat-denatured luciferase and suppression of polyQ aggregation. DNAJB1 promoted efficient luciferase refolding when paired with HSP70, classifying it as a foldase-type co-chaperone. Unlike DNAJB6 and DNAJB8, which have independent holdase/anti-aggregation activity, DNAJB1 primarily functions by delivering substrates to HSP70 and stimulating HSP70 ATPase activity for the protein folding cycle. UniProt confirms that DNAJB1 stimulates ATP hydrolysis and the folding of unfolded proteins mediated by HSPA1A/B in vitro (PMID:24318877). The appropriate replacement is GO:0044183 (protein folding chaperone), which accurately captures DNAJB1's role in binding proteins to assist folding as part of the HSP70 machine. Reason: GO:0051082 is scheduled for obsoletion (go-ontology#30962), with the recommended replacement being GO:0044183 (protein folding chaperone) for foldase-type chaperones or holdase chaperone activity for holdases. Hageman et al. (PMID:21231916) is the key reference for this IDA annotation. The paper showed that DNAJB1 belongs to the foldase class of J-domain co-chaperones: it promotes luciferase refolding when combined with HSP70 but is a poor suppressor of polyQ aggregation. This functional classification is consistent with DNAJB1's known mechanism as a class II J-domain protein that stimulates HSP70 ATPase activity and delivers substrates to the HSP70 folding machinery. Additionally, DNAJB1 is a component of the Hsp70 disaggregation machinery, working with Hsp70 and HSPA4 to disassemble protein aggregates in an ATP-dependent process. The correct replacement term is GO:0044183 (protein folding chaperone), defined as binding to a protein or protein-containing complex to assist the protein folding process. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:21231916 Overexpressed chaperones that suppressed polyQ aggregation were found not to be able to stimulate luciferase refolding. Inversely, chaperones that supported luciferase refolding were poor suppressors of polyQ aggregation. PMID:21231916 Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding genes and most of the corresponding proteins are localized in the cytosol. To test for possible functional differences and/or substrate specificity, we assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment.
GO:0090084 negative regulation of inclusion body assembly	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	KEEP AS NON CORE	Summary: Hageman et al. (PMID:21231916) showed that DNAJB1 overexpression suppresses polyQ aggregation (inclusion body assembly), though it was a poor suppressor compared to holdase-type chaperones like DNAJB6 and DNAJB8. The paper states that chaperones that supported luciferase refolding were poor suppressors of polyQ aggregation, and DNAJB1 falls into the foldase category. Reason: DNAJB1 can negatively regulate inclusion body assembly but is not primarily an anti-aggregation chaperone. Hageman et al. (PMID:21231916) showed that foldase-type chaperones like DNAJB1 are poor suppressors of polyQ aggregation compared to holdases like DNAJB6/DNAJB8. The annotation is valid but represents a minor aspect of DNAJB1 function. Keep as non-core. Supporting Evidence: PMID:21231916 Overexpressed chaperones that suppressed polyQ aggregation were found not to be able to stimulate luciferase refolding. Inversely, chaperones that supported luciferase refolding were poor suppressors of polyQ aggregation.
GO:0005634 nucleus	HDA PMID:21630459 Proteomic characterization of the human sperm nucleus.	ACCEPT	Summary: PMID:21630459 is a proteomic characterization of the human sperm nucleus. DNAJB1 was identified in the sperm nuclear proteome by mass spectrometry. This is consistent with known nuclear localization of DNAJB1. Reason: Nuclear localization of DNAJB1 is well-established from UniProt (stress-induced translocation) and HPA immunofluorescence. Detection in the sperm nucleus proteome by mass spectrometry provides additional supporting evidence.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-3371467	ACCEPT	Summary: Reactome R-HSA-3371467 models SIRT1 deacetylation of HSF1. DNAJB1 is included in this pathway as part of the HSF1 regulatory complex in the nucleoplasm. Reason: Nucleoplasm localization is consistent with DNAJB1's role in HSF1 regulation in the nucleus during heat shock attenuation.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-3371518	ACCEPT	Summary: Reactome R-HSA-3371518 models SIRT1 binding to HSF1. DNAJB1 participates in the nucleoplasmic HSF1 regulatory complex. Reason: Nucleoplasm localization during heat shock response regulation is consistent with DNAJB1's known stress-induced nuclear translocation and HSF1 binding activity.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-3371554	ACCEPT	Summary: Reactome R-HSA-3371554 models HSF1 acetylation at Lys80. DNAJB1 participates in this HSF1 regulatory pathway in the nucleoplasm. Reason: DNAJB1 is part of the HSF1 regulatory complex in the nucleoplasm during heat shock attenuation. Consistent with known biology.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5082356	ACCEPT	Summary: Reactome R-HSA-5082356 models HSF1-mediated gene expression. DNAJB1 is placed in the nucleoplasm as part of the HSF1 attenuation mechanism. Reason: DNAJB1 localizes to the nucleoplasm during the heat shock response to participate in HSF1 regulation. Consistent with UniProt and PMID:9499401.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5082369	ACCEPT	Summary: Reactome R-HSA-5082369 models acetylated HSF1 dissociation from DNA. DNAJB1 is part of the HSF1 attenuation complex in the nucleoplasm. Reason: DNAJB1 nucleoplasm localization is consistent with its role in HSF1 regulation during heat shock attenuation.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5082384	ACCEPT	Summary: Reactome R-HSA-5082384 specifically models HSP70:DNAJB1 binding HSF1 in the nucleoplasm. Shi et al. (PMID:9499401) showed that Hsp70 and Hdj1 interact with the HSF1 activation domain and repress transcription. Reason: This Reactome entry directly models the DNAJB1-HSP70-HSF1 interaction in the nucleoplasm, which is a well-characterized mechanism of heat shock attenuation (PMID:9499401).
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5251955	ACCEPT	Summary: Reactome R-HSA-5251955 models HSP40s activating HSP70 ATPase activity in the nucleoplasm. DNAJB1 is explicitly listed as one of the HSP40s that stimulates HSP70 ATPase activity in this compartment. Reason: Nucleoplasm localization is consistent with DNAJB1's nuclear translocation under heat shock and its ATPase activator function in the nucleoplasm.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: PMID:19056867 is a large-scale proteomics study of urinary exosomes. Detection of DNAJB1 in exosomes by mass spectrometry may represent passive inclusion rather than specific exosomal targeting. Reason: Detection in extracellular exosomes by proteomics (PMID:19056867) is valid but represents a non-specific finding. Many cytosolic proteins are found in exosomes without specific functional significance. Keep as non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-5251959	ACCEPT	Summary: Reactome R-HSA-5251959 models HSP40s activating HSP70 ATPase activity in the cytosol. DNAJB1 is one of the HSP40s that activates HSP70 ATPase in the cytosol. Reason: Cytosol is the primary location of DNAJB1. The Reactome pathway correctly places DNAJB1 ATPase activator function in the cytosol.
GO:0005829 cytosol	TAS Reactome:R-HSA-5690245	ACCEPT	Summary: Reactome R-HSA-5690245 models the binding of phosphorylated MAPKAPK5 to DNAJB1 in the cytosol. Cytosolic localization is consistent with known DNAJB1 biology. Reason: Cytosol localization is consistent with DNAJB1 primary localization. The Reactome pathway for MAPKAPK5 binding to DNAJB1 correctly places this interaction in the cytosol.
GO:0006457 protein folding	IDA PMID:18620420 Role of the cochaperone Tpr2 in Hsp90 chaperoning.	ACCEPT	Summary: Moffatt et al. (PMID:18620420) studied the role of the cochaperone Tpr2 in Hsp90 chaperoning. The paper mentions that Tpr2 replaced type I and II J proteins (including DNAJB1-type) in Hsp90-dependent chaperoning. DNAJB1 participation in protein folding through the Hsp90 chaperone cycle is consistent with its co-chaperone function. Reason: Protein folding is a core function of DNAJB1. PMID:18620420 provides evidence that J proteins including type II (DNAJB1 class) participate in Hsp90-dependent protein folding. While the paper focuses on Tpr2, it demonstrates DNAJB1-class J protein involvement in the chaperone folding cycle. Supporting Evidence: PMID:18620420 Tpr2 replaced type I and II J proteins in the Hsp90-dependent chaperoning of the PR and the protein kinase, Chk1.
GO:0006986 response to unfolded protein	TAS PMID:8975727 Genomic cloning of a human heat shock protein 40 (Hsp40) gen...	ACCEPT	Summary: Hata et al. (PMID:8975727) cloned the genomic DNA for human Hsp40 (DNAJB1) and characterized its gene structure. The 5-prime region contains typical heat shock elements, indicating stress-responsive expression consistent with response to unfolded protein. Reason: DNAJB1 (Hsp40) is a heat shock protein with heat shock elements in its promoter (PMID:8975727), indicating stress-responsive induction. As a co-chaperone for HSP70 that assists in folding unfolded proteins, response to unfolded protein is an appropriate biological process annotation. Supporting Evidence: PMID:8975727 The 5' region of the gene is highly GC rich, and there are multiple basal elements for transcription factors including typical heat shock elements.

Core Functions

DNAJB1 is a class B J-domain co-chaperone (foldase-type) that binds unfolded/misfolded protein substrates via its C-terminal beta-sandwich domains (CTD-I and CTD-II) and delivers them to HSP70 for productive ATP-dependent refolding. DNAJB1 stimulates the ATPase activity of HSP70 via its J-domain HPD motif and promotes substrate release and refolding. A distinctive feature of DNAJB1 is G/F-mediated autoinhibition of its J-domain, which is relieved by a secondary contact between Hsp70's EEVD motif and a positively charged groove in CTD-I, enabling productive Hsp70 engagement (DOI:10.1016/j.tcb.2022.05.004). DNAJB1 also participates in disaggregation by remaining associated with protein aggregates and scaffolding multiple Hsp70 molecules through JDP hetero-oligomerization. Classified as a foldase rather than holdase based on its ability to support luciferase refolding and poor suppression of polyQ aggregation (PMID:21231916).

Molecular Function:

protein folding chaperone

Directly Involved In:

protein folding positive regulation of protein folding response to unfolded protein cellular response to heat regulation of cellular response to heat

Cellular Locations:

cytosol nucleoplasm nucleolus

Supporting Evidence:

PMID:21231916
chaperones that supported luciferase refolding were poor suppressors of polyQ aggregation.
PMID:24318877
we combined the Hsp70-NEF pairs with cochaperones of the J protein family (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The activity of the combinations in ATPase and luciferase refolding assays were dependent on the identity and stoichiometry of both the J protein and NEF

DNAJB1 stimulates the intrinsic ATPase activity of HSP70 family members (HSPA1A/B) through its J-domain HPD motif, which docks on ATP-bound Hsp70 at the interdomain linker and positions the HPD motif to activate Hsp70's catalytic center (DOI:10.1016/j.tcb.2022.05.004). This stimulation shifts Hsp70 to a high-affinity client-binding state ("ultra-affinity"), driving the HSP70 chaperone cycle for substrate binding, folding, and release. Nucleotide exchange factors then promote ADP release to reset the cycle. Directly demonstrated in vitro using purified components with varying Hsp70-NEF combinations (PMID:24318877). The J-domain activity is subject to G/F-mediated autoinhibition in class B JDPs, requiring Hsp70 EEVD-mediated relief for full activation.

Molecular Function:

ATPase activator activity

Directly Involved In:

protein folding

Cellular Locations:

cytosol nucleoplasm

Supporting Evidence:

PMID:24318877
we combined the Hsp70-NEF pairs with cochaperones of the J protein family (DnaJA1, DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The activity of the combinations in ATPase and luciferase refolding assays were dependent on the identity and stoichiometry of both the J protein and NEF
PMID:23921388
Hsp70 proteins constitute an evolutionarily conserved protein family of ATP-dependent molecular chaperones involved in a wide range of biological processes.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:17024176

A novel HSF1-mediated death pathway that is suppressed by heat shock proteins.

PMID:18620420

Role of the cochaperone Tpr2 in Hsp90 chaperoning.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

PMID:20060297

Chaperone-assisted selective autophagy is essential for muscle maintenance.

PMID:21044950

Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.

PMID:21163940

Interactome mapping suggests new mechanistic details underlying Alzheimer's disease.

PMID:21231916

The diverse members of the mammalian HSP70 machine show distinct chaperone-like activities.

PMID:21630459

Proteomic characterization of the human sperm nucleus.

PMID:23921388

Identification and characterization of a novel human methyltransferase modulating Hsp70 protein function through lysine methylation.

PMID:24318877

Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70) generates functionally distinct complexes in vitro.

PMID:25036637

A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.

PMID:25468996

E-cadherin interactome complexity and robustness resolved by quantitative proteomics.

PMID:27120771

Polyhydramnios, Transient Antenatal Bartter's Syndrome, and MAGED2 Mutations.

PMID:27173435

An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:36931259

A central chaperone-like role for 14-3-3 proteins in human cells.

PMID:8975727

Genomic cloning of a human heat shock protein 40 (Hsp40) gene (HSPF1) and its chromosomal localization to 19p13.2.

PMID:9499401

Molecular chaperones as HSF1-specific transcriptional repressors.

Reactome:R-HSA-3371453

Regulation of HSF1-mediated heat shock response

Reactome:R-HSA-3371467

SIRT1 deacetylates HSF1

Reactome:R-HSA-3371518

SIRT1 binds to HSF1

Reactome:R-HSA-3371554

HSF1 acetylation at Lys80

Reactome:R-HSA-5082356

HSF1-mediated gene expression

Reactome:R-HSA-5082369

Acetylated HSF1 dissociates from DNA

Reactome:R-HSA-5082384

HSP70:DNAJB1 binds HSF1

Reactome:R-HSA-5251955

HSP40s activate intrinsic ATPase activity of HSP70s in the nucleoplasm

Reactome:R-HSA-5251959

HSP40s activate intrinsic ATPase activity of HSP70s in the cytosol

Reactome:R-HSA-5690245

p-T182 MAPKAPK5 binds DNAJB1

Reactome:R-HSA-5690250

p-T182-MAPKAPK5 phoshphorylates DNAJB1

DOI:10.1016/j.tcb.2022.05.004

J-domain protein chaperone circuits in proteostasis and disease.

Class B JDPs (including DNAJB1) have G/F-mediated autoinhibition of the J-domain; interaction between Hsp70's EEVD motif and DNAJB1 CTD-I relieves this autoinhibition for productive Hsp70 engagement.
JDP scaffolding and hetero-oligomerization, including DNAJB1 participation, creates potent Hsp70-based disaggregases; DNAJB1 remains associated with aggregates to recruit multiple Hsp70 molecules.

DOI:10.3390/ijms222413527

Regulation of p53 and cancer signaling by heat shock protein 40/J-domain protein family members.

DNAJB1/HDJ1 binds and stabilizes MDM2 and destabilizes PDCD5, modulating p53-mediated apoptosis; can also support mutant p53 gain-of-function phenotypes in context-dependent manner.

📚 Additional Documentation

Deep Research Falcon

(DNAJB1-deep-research-falcon.md)

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organism_full: Homo sapiens (Human).
protein_family: Not specified in UniProt
protein_domains: DnaJ_C. (IPR002939); DnaJ_domain. (IPR001623); DnaJ_domain_CS.
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P25685
Protein Description: RecName: Full=DnaJ homolog subfamily B member 1; AltName: Full=DnaJ protein homolog 1; AltName: Full=Heat shock 40 kDa protein 1; Short=HSP40; Short=Heat shock protein 40; AltName: Full=Human DnaJ protein 1; Short=hDj-1;
Gene Information: Name=DNAJB1; Synonyms=DNAJ1, HDJ1, HSPF1;
Organism (full): Homo sapiens (Human).
Protein Family: Not specified in UniProt
Key Domains: DnaJ_C. (IPR002939); DnaJ_domain. (IPR001623); DnaJ_domain_CS. (IPR018253); DnaJ_subfamily_B. (IPR051339); HSP40/DnaJ_pept-bd. (IPR008971)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "DNAJB1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'DNAJB1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene DNAJB1 (gene ID: DNAJB1, UniProt: P25685) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P25685
Protein Description: RecName: Full=DnaJ homolog subfamily B member 1; AltName: Full=DnaJ protein homolog 1; AltName: Full=Heat shock 40 kDa protein 1; Short=HSP40; Short=Heat shock protein 40; AltName: Full=Human DnaJ protein 1; Short=hDj-1;
Gene Information: Name=DNAJB1; Synonyms=DNAJ1, HDJ1, HSPF1;
Organism (full): Homo sapiens (Human).
Protein Family: Not specified in UniProt
Key Domains: DnaJ_C. (IPR002939); DnaJ_domain. (IPR001623); DnaJ_domain_CS. (IPR018253); DnaJ_subfamily_B. (IPR051339); HSP40/DnaJ_pept-bd. (IPR008971)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "DNAJB1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene DNAJB1 (gene ID: DNAJB1, UniProt: P25685) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Title: Functional annotation research report for human DNAJB1 (UniProt P25685)

Executive summary and target verification

DNAJB1 (UniProt P25685; aliases HDJ1/HSP40/DNAJ1) encodes a canonical cytosolic/nuclear class B J-domain protein (JDP; “Hsp40”) that functions primarily as a co-chaperone for Hsp70 family chaperones by (i) recognizing non-native proteins through its C-terminal client-binding domains and (ii) stimulating Hsp70 ATP hydrolysis through its N-terminal J-domain, thereby coupling client capture to the Hsp70 chaperone cycle. (kaida2021regulationofp53 pages 2-4, zhang2023jdomainproteinchaperone pages 3-4)

A frequent point of confusion is that “DNAJB1” also appears in the oncogenic DNAJB1–PRKACA gene fusion that drives fibrolamellar carcinoma (FLC). The fusion is a distinct entity (a chimeric oncoprotein/oncokinase) and should not be conflated with the wild-type DNAJB1 co-chaperone. (kaida2021regulationofp53 pages 6-8, song2024modelsoffibrolamellar pages 1-2)

Key concepts and definitions (current understanding)

2.1. J-domain proteins (Hsp40/JDPs) and class B architecture

J-domain proteins (JDPs; historically called Hsp40s) are co-chaperones that specify Hsp70 functions. Their defining element is the ~70 amino-acid J-domain containing a conserved HPD motif, which is required to stimulate Hsp70 ATPase activity. (zhang2023jdomainproteinchaperone pages 13-14, zhang2023jdomainproteinchaperone pages 3-4)

Class B JDPs (the DNAJB family) have an N-terminal J-domain, an adjacent glycine/phenylalanine-rich (G/F-rich) region, and C-terminal β-sandwich client-binding domains (CTD-I and CTD-II) plus a dimerization domain; class B members notably lack the class A zinc-finger-like region. DNAJB1/HDJ1 is among class B proteins described as retaining CTD-II and a dimerization domain. (kaida2021regulationofp53 pages 2-4, zhang2023jdomainproteinchaperone pages 4-6)

A visual summary of class B architecture and a structural view using DNAJB1 as a representative are shown in Zhang et al. 2023 (Figure 3). (zhang2023jdomainproteinchaperone media 92edd5fb, zhang2023jdomainproteinchaperone media 87ff823b)

2.2. Mechanistic role of DNAJB1 in the Hsp70 ATPase cycle

In the canonical Hsp70 cycle, the J-domain docks on ATP-bound Hsp70 (at the interdomain linker) and positions the HPD motif to activate Hsp70’s catalytic center. This stimulates ATP hydrolysis, shifting Hsp70 to a high-affinity client-binding state (“ultra-affinity”), facilitating client capture and iterative refolding/unfolding cycles; nucleotide exchange factors then promote ADP release to reset the cycle. (zhang2023jdomainproteinchaperone pages 3-4)

DNAJB1 also participates in regulatory interactions that tune this cycle. For example, class B JDPs can show G/F-mediated autoinhibition of the J-domain; in DNAJB1/HDJ1, interaction between Hsp70’s C-terminal EEVD motif and a groove in DNAJB1 CTD-I is described as relieving this inhibition and enabling productive Hsp70 engagement (a mechanism discussed in the context of disaggregation activity). (kaida2021regulationofp53 pages 6-8, zhang2023jdomainproteinchaperone pages 8-9)

2.3. Primary functional annotation (what DNAJB1 “does”)

DNAJB1 is not an enzyme that catalyzes a defined chemical reaction; rather, it is an ATPase-cycle regulator and substrate-targeting factor for Hsp70. Its primary biochemical function is to (i) bind non-native protein clients via C-terminal regions and (ii) activate Hsp70 ATP hydrolysis via its J-domain/HPD motif, thereby increasing Hsp70 client-binding and enabling folding/refolding, disaggregation, or triage to degradation pathways depending on context. (kaida2021regulationofp53 pages 2-4, zhang2023jdomainproteinchaperone pages 3-4)

2.4. Subcellular localization (current evidence level)

The JDP family spans many compartments (e.g., ER, mitochondria, cytosol/nucleus), but the evidence assembled here does not provide a DNAJB1-specific steady-state localization statement beyond placing DNAJB1 as a prototypical (non-organelle-targeted) class B JDP used as a representative in cytosolic Hsp70 circuits and aggregate-associated recruitment of Hsp70. (zhang2023jdomainproteinchaperone pages 28-32, zhang2023jdomainproteinchaperone pages 3-4)

Biological processes and pathways

3.1. Proteostasis networks and stress responses

JDP–Hsp70 systems are central to cellular proteostasis and are transcriptionally tuned by stress responses such as heat shock and unfolded protein response programs, with dysregulation linked to neurodegeneration and cancer. (zhang2023jdomainproteinchaperone pages 4-6)

Within proteostasis, DNAJB1 has been highlighted as capable of remaining associated with aggregates to recruit multiple Hsp70 molecules, consistent with a role in assembling effective disaggregation/processing machinery on aggregated substrates. (zhang2023jdomainproteinchaperone pages 3-4)

3.2. p53/MDM2 axis and cancer-relevant signaling

A 2021 review summarizes evidence that DNAJB1/HDJ1 can functionally intersect with p53 signaling via complexes with HSC70/HSP70 and ATP. DNAJB1/HDJ1 has been reported to bind and stabilize MDM2 and to modulate p53 regulation, and it has also been reported to destabilize PDCD5, suppressing p53-mediated apoptosis in some contexts; other contexts suggest DNAJB1/HDJ1 can support mutant p53 gain-of-function phenotypes, highlighting strong context dependence (wild-type vs mutant p53; cellular setting). (kaida2021regulationofp53 pages 6-8, kaida2021regulationofp53 pages 16-17, kaida2021regulationofp53 pages 8-9)

Recent developments and latest research (prioritizing 2023–2024)

4.1. 2023: refined mechanistic models for DNAJB1 regulation within Hsp70–JDP circuits

A 2023 Trends in Cell Biology review emphasizes that DNAJB1 is regulated by multiple intrinsic autoinhibitory elements and that a secondary contact between the Hsp70 EEVD motif and a positively charged groove in DNAJB1 CTD-I can relieve autoinhibition, although the precise trigger remains unresolved. The same review discusses how JDP scaffolding/hetero-oligomerization (including DNAJB1 participation) can create potent Hsp70-based disaggregases, underscoring network-level rather than single-protein regulation. (zhang2023jdomainproteinchaperone pages 8-9)

4.2. 2024: DNAJB1–PRKACA fusion as a model of “DNAJB1 sequence repurposed” in cancer

Although distinct from wild-type DNAJB1 function, the DNAJB1–PRKACA fusion dominates DNAJB1-related translational research in 2023–2024.

(i) Multi-omics and tumor classification: A 2024 Nature Communications study analyzed RNA-seq from 1,412 liver tumors and assembled 220 FLC/FLC-like samples (127 newly sequenced plus 91 reprocessed external), deriving an FLC transcriptional signature (693 genes: 287 up, 406 down) from 81 matched tumor-normal pairs. It reported that primary tumors vs normal differed in 6.5% of transcripts (n=3,506), while metastases vs primaries differed in only 0.6% (n=310), and showed strong concordance between proteome and transcriptome (R2=0.8). (requena2024livercancermultiomics pages 1-2, requena2024livercancermultiomics pages 2-3)

(ii) Downstream transcriptional mediators: A 2024 PLOS Genetics study identified the primate-restricted lncRNA LINC00473 as among the most upregulated genes in FLC tumors; its expression was strongly suppressed by RNAi-mediated inhibition of the DNAJB1–PRKACA fusion. Functional loss/gain experiments supported that LINC00473 promotes tumor growth, suppresses apoptosis, and alters metabolism (promoting glycolysis; affecting spare respiratory capacity). (ma2024dnajb1prkacafusionproteinregulated pages 1-4)

(iii) Tumor immunology/neoantigens: A 2024 Cell Reports Medicine study emphasized that DNAJB1–PRKACA is present in >90% of FLC cases and thus represents a shared neoantigen target. The authors reported that endogenous fusion-specific CD8 T cell responses are rare, but identified two functional fusion-specific TCRs, one of which showed strong anti-tumor activity in vivo, supporting TCR-based cellular therapy development. (kirk2024dnajb1prkacafusionneoantigens pages 1-3)

Current applications and real-world implementations

5.1. Diagnostics: DNAJB1–PRKACA fusion detection in fibrolamellar carcinoma

A 2024 review of FLC models states that “almost all” FLC tumors have the DNAJB1–PRKACA fusion and that the fusion is accepted as a diagnostic criterion, described as an extremely sensitive and specific molecular marker in the FLC diagnostic setting (noting that other literature has reported rare detection in non-FLC oncocytic neoplasms). (song2024modelsoffibrolamellar pages 1-2, hackenbruch2024fusionvac2201aphase pages 11-11)

5.2. Therapeutics in development: vaccines, TCR-T, and nucleic-acid therapeutics targeting the fusion

Peptide vaccine + checkpoint blockade (clinical trial design, 2024): FusionVAC22_01 is a phase I, open-label, multicenter trial evaluating a DNAJB1–PRKACA fusion transcript-based peptide vaccine (Fusion-VAC-XS15) combined with anti–PD-L1 therapy (atezolizumab). Trial registration: EU CT 2022-502869-17-01; ClinicalTrials.gov NCT05937295. The design includes two vaccine doses 4 weeks apart and atezolizumab every 4 weeks through a 54-week treatment phase. (hackenbruch2024fusionvac2201aphase pages 1-2)

The same trial report provides population-scale “implementability” statistics: predicted binding to 1,290 HLA class II alleles and inclusion of sequences from 13 frequent HLA-I alleles, covering ~96.6% of the European population and ~93.8% worldwide. Planned enrollment is n=20. (hackenbruch2024fusionvac2201aphase pages 7-8)

GalNAc-siRNA fusion junction targeting (preclinical, 2024): A 2024 Molecular Therapy study designed chemically stabilized GalNAc-conjugated siRNAs against the DNAJB1::PRKACA fusion junction to enable liver uptake (ASGR-mediated). In Huh7 cells expressing the fusion and in multiple FLC patient-derived xenograft models, these siRNAs preferentially targeted the fusion over native DNAJB1/PRKACA, achieved productive uptake, and produced durable inhibition of PDX growth in vivo with no detectable toxicities reported. (neumayer2024galnacconjugatedsirnatargeting pages 1-2)

TCR-based cell therapy (preclinical, 2024): Fusion-specific TCR discovery and validation provides a path to engineered TCR-T approaches. The 2024 Cell Reports Medicine study identified two functional DNAJB1–PRKACA fusion-specific TCRs; one showed strong in vivo anti-tumor activity. (kirk2024dnajb1prkacafusionneoantigens pages 1-3)

Expert opinion and analysis (authoritative synthesis)

A key consensus view from high-level reviews is that JDPs such as DNAJB1 operate as network “catalysts” that confer substrate specificity and functional diversity on Hsp70s, with regulation distributed across domain architecture, autoinhibitory intramolecular contacts, and co-assembly/scaffolding mechanisms; accordingly, DNAJB1 function is best understood as circuit behavior rather than a single binary activity. (zhang2023jdomainproteinchaperone pages 4-6, zhang2023jdomainproteinchaperone pages 8-9)

In cancer biology, expert synthesis emphasizes context dependence of DNAJB1/HDJ1 interactions with p53 pathway components, with evidence supporting both pro-survival and potentially tumor-suppressive outcomes depending on p53 status and experimental setting, underscoring the need for client- and genotype-specific functional studies when interpreting DNAJB1 as a therapeutic target. (kaida2021regulationofp53 pages 8-9, kaida2021regulationofp53 pages 6-8)

Quantitative statistics and data highlights (recent)

Fibrolamellar carcinoma (fusion-driven disease context)

Incidence: ~0.02 per 100,000 annually in the US. (kirk2024dnajb1prkacafusionneoantigens pages 1-3)

Fusion prevalence: DNAJB1–PRKACA present in >90% of FLC cases (driver/neoantigen rationale). (kirk2024dnajb1prkacafusionneoantigens pages 1-3)

Mortality: estimated 60–80% of patients ultimately succumb (as reported in 2024 Cell Reports Medicine). (kirk2024dnajb1prkacafusionneoantigens pages 1-3)

5-year survival: ~45% (reported in the 2024 FusionVAC22_01 clinical trial article background). (hackenbruch2024fusionvac2201aphase pages 1-2)

Multi-omics cohort sizes and tumor similarity (2024 Nature Communications): 1,412 liver tumor RNA-seq samples analyzed; 220 FLC/FLC-like samples assembled; 693-gene signature; 6.5% transcripts altered in primary vs normal (n=3,506) vs 0.6% altered in metastasis vs primary (n=310); proteome–transcriptome concordance R2=0.8. (requena2024livercancermultiomics pages 1-2, requena2024livercancermultiomics pages 2-3)

Practical notes for functional annotation (what to record in a gene card)

Molecular function: “Hsp70 co-chaperone; stimulates Hsp70 ATPase via J-domain HPD motif; binds non-native client proteins via CTD-I/CTD-II; supports disaggregation/folding/triage depending on co-chaperone network context.” (kaida2021regulationofp53 pages 2-4, zhang2023jdomainproteinchaperone pages 3-4)

Cellular component: broadly consistent with cytosolic/nuclear JDP circuits (no organelle-targeting described in the evidence collected here); may associate with protein aggregates as a platform for Hsp70 recruitment. (zhang2023jdomainproteinchaperone pages 3-4)

Biological processes/pathways: proteostasis and stress response; p53/MDM2 axis modulation; broader cancer-relevant signaling is context-dependent. (kaida2021regulationofp53 pages 6-8, zhang2023jdomainproteinchaperone pages 4-6)

Caution/ambiguity: Separate all annotations for wild-type DNAJB1 from those for the DNAJB1–PRKACA fusion oncoprotein used in FLC diagnostics and translational programs. (kaida2021regulationofp53 pages 6-8, song2024modelsoffibrolamellar pages 1-2)

Key cited sources (with dates and URLs)

Zhang R, Malinverni D, Cyr DM, De Los Rios P, Nillegoda NB. “J-domain protein chaperone circuits in proteostasis and disease.” Trends in Cell Biology. Publication month: Jan 2023. https://doi.org/10.1016/j.tcb.2022.05.004 (zhang2023jdomainproteinchaperone pages 4-6, zhang2023jdomainproteinchaperone pages 3-4, zhang2023jdomainproteinchaperone pages 8-9, zhang2023jdomainproteinchaperone media 92edd5fb)

Kaida A, Iwakuma T. “Regulation of p53 and Cancer Signaling by Heat Shock Protein 40/J-Domain Protein Family Members.” Int J Mol Sci. Publication month: Dec 2021. https://doi.org/10.3390/ijms222413527 (kaida2021regulationofp53 pages 6-8, kaida2021regulationofp53 pages 8-9)

Song J, Lu M, He Z, Zhang W. “Models of fibrolamellar carcinomas, tools for evaluation of a new era of treatments.” Frontiers in Immunology. Publication month: Nov 2024. https://doi.org/10.3389/fimmu.2024.1459942 (song2024modelsoffibrolamellar pages 1-2)

Requena D, Medico JA, Soto-Ugaldi LF, et al. “Liver cancer multiomics reveals diverse protein kinase A disruptions convergently produce fibrolamellar hepatocellular carcinoma.” Nature Communications. Publication month: Dec 2024. https://doi.org/10.1038/s41467-024-55238-2 (requena2024livercancermultiomics pages 1-2, requena2024livercancermultiomics pages 2-3)

Ma RK, Tsai P-Y, Farghli AR, et al. “DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma.” PLOS Genetics. Publication month: Jun 2024. https://doi.org/10.1101/2023.06.02.543290 (ma2024dnajb1prkacafusionproteinregulated pages 1-4)

Kirk AM, Crawford JC, Chou C-H, et al. “DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma.” Cell Reports Medicine. Publication month: Mar 2024. https://doi.org/10.1016/j.xcrm.2024.101469 (kirk2024dnajb1prkacafusionneoantigens pages 1-3)

Neumayer C, Ng D, Requena D, et al. “GalNAc-conjugated siRNA targeting the DNAJB1-PRKACA fusion junction in fibrolamellar hepatocellular carcinoma.” Molecular Therapy. Publication month: Jan 2024. https://doi.org/10.1016/j.ymthe.2023.11.012 (neumayer2024galnacconjugatedsirnatargeting pages 1-2)

Hackenbruch C, Bauer J, Heitmann JS, et al. “FusionVAC22_01: a phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition…” Frontiers in Oncology. Publication month: Mar 2024. https://doi.org/10.3389/fonc.2024.1367450 ; ClinicalTrials.gov NCT05937295 (hackenbruch2024fusionvac2201aphase pages 1-2, hackenbruch2024fusionvac2201aphase pages 7-8)

References

(kaida2021regulationofp53 pages 2-4): Atsushi Kaida and Tomoo Iwakuma. Regulation of p53 and cancer signaling by heat shock protein 40/j-domain protein family members. International Journal of Molecular Sciences, 22:13527, Dec 2021. URL: https://doi.org/10.3390/ijms222413527, doi:10.3390/ijms222413527. This article has 35 citations.
(zhang2023jdomainproteinchaperone pages 3-4): Ruobing Zhang, Duccio Malinverni, Douglas M. Cyr, Paolo De Los Rios, and Nadinath B. Nillegoda. J-domain protein chaperone circuits in proteostasis and disease. Jan 2023. URL: https://doi.org/10.1016/j.tcb.2022.05.004, doi:10.1016/j.tcb.2022.05.004. This article has 60 citations and is from a domain leading peer-reviewed journal.
(kaida2021regulationofp53 pages 6-8): Atsushi Kaida and Tomoo Iwakuma. Regulation of p53 and cancer signaling by heat shock protein 40/j-domain protein family members. International Journal of Molecular Sciences, 22:13527, Dec 2021. URL: https://doi.org/10.3390/ijms222413527, doi:10.3390/ijms222413527. This article has 35 citations.
(song2024modelsoffibrolamellar pages 1-2): Jinjia Song, Mengqi Lu, Zhiying He, and Wencheng Zhang. Models of fibrolamellar carcinomas, tools for evaluation of a new era of treatments. Frontiers in Immunology, Nov 2024. URL: https://doi.org/10.3389/fimmu.2024.1459942, doi:10.3389/fimmu.2024.1459942. This article has 4 citations and is from a peer-reviewed journal.
(zhang2023jdomainproteinchaperone pages 13-14): Ruobing Zhang, Duccio Malinverni, Douglas M. Cyr, Paolo De Los Rios, and Nadinath B. Nillegoda. J-domain protein chaperone circuits in proteostasis and disease. Jan 2023. URL: https://doi.org/10.1016/j.tcb.2022.05.004, doi:10.1016/j.tcb.2022.05.004. This article has 60 citations and is from a domain leading peer-reviewed journal.
(zhang2023jdomainproteinchaperone pages 4-6): Ruobing Zhang, Duccio Malinverni, Douglas M. Cyr, Paolo De Los Rios, and Nadinath B. Nillegoda. J-domain protein chaperone circuits in proteostasis and disease. Jan 2023. URL: https://doi.org/10.1016/j.tcb.2022.05.004, doi:10.1016/j.tcb.2022.05.004. This article has 60 citations and is from a domain leading peer-reviewed journal.
(zhang2023jdomainproteinchaperone media 92edd5fb): Ruobing Zhang, Duccio Malinverni, Douglas M. Cyr, Paolo De Los Rios, and Nadinath B. Nillegoda. J-domain protein chaperone circuits in proteostasis and disease. Jan 2023. URL: https://doi.org/10.1016/j.tcb.2022.05.004, doi:10.1016/j.tcb.2022.05.004. This article has 60 citations and is from a domain leading peer-reviewed journal.
(zhang2023jdomainproteinchaperone media 87ff823b): Ruobing Zhang, Duccio Malinverni, Douglas M. Cyr, Paolo De Los Rios, and Nadinath B. Nillegoda. J-domain protein chaperone circuits in proteostasis and disease. Jan 2023. URL: https://doi.org/10.1016/j.tcb.2022.05.004, doi:10.1016/j.tcb.2022.05.004. This article has 60 citations and is from a domain leading peer-reviewed journal.
(zhang2023jdomainproteinchaperone pages 8-9): Ruobing Zhang, Duccio Malinverni, Douglas M. Cyr, Paolo De Los Rios, and Nadinath B. Nillegoda. J-domain protein chaperone circuits in proteostasis and disease. Jan 2023. URL: https://doi.org/10.1016/j.tcb.2022.05.004, doi:10.1016/j.tcb.2022.05.004. This article has 60 citations and is from a domain leading peer-reviewed journal.
(zhang2023jdomainproteinchaperone pages 28-32): Ruobing Zhang, Duccio Malinverni, Douglas M. Cyr, Paolo De Los Rios, and Nadinath B. Nillegoda. J-domain protein chaperone circuits in proteostasis and disease. Jan 2023. URL: https://doi.org/10.1016/j.tcb.2022.05.004, doi:10.1016/j.tcb.2022.05.004. This article has 60 citations and is from a domain leading peer-reviewed journal.
(kaida2021regulationofp53 pages 16-17): Atsushi Kaida and Tomoo Iwakuma. Regulation of p53 and cancer signaling by heat shock protein 40/j-domain protein family members. International Journal of Molecular Sciences, 22:13527, Dec 2021. URL: https://doi.org/10.3390/ijms222413527, doi:10.3390/ijms222413527. This article has 35 citations.
(kaida2021regulationofp53 pages 8-9): Atsushi Kaida and Tomoo Iwakuma. Regulation of p53 and cancer signaling by heat shock protein 40/j-domain protein family members. International Journal of Molecular Sciences, 22:13527, Dec 2021. URL: https://doi.org/10.3390/ijms222413527, doi:10.3390/ijms222413527. This article has 35 citations.
(requena2024livercancermultiomics pages 1-2): David Requena, Jack A. Medico, Luis F. Soto-Ugaldi, Mahsa Shirani, James A. Saltsman, Michael S. Torbenson, Philip Coffino, and Sanford M. Simon. Liver cancer multiomics reveals diverse protein kinase a disruptions convergently produce fibrolamellar hepatocellular carcinoma. Nature Communications, Dec 2024. URL: https://doi.org/10.1038/s41467-024-55238-2, doi:10.1038/s41467-024-55238-2. This article has 8 citations and is from a highest quality peer-reviewed journal.
(requena2024livercancermultiomics pages 2-3): David Requena, Jack A. Medico, Luis F. Soto-Ugaldi, Mahsa Shirani, James A. Saltsman, Michael S. Torbenson, Philip Coffino, and Sanford M. Simon. Liver cancer multiomics reveals diverse protein kinase a disruptions convergently produce fibrolamellar hepatocellular carcinoma. Nature Communications, Dec 2024. URL: https://doi.org/10.1038/s41467-024-55238-2, doi:10.1038/s41467-024-55238-2. This article has 8 citations and is from a highest quality peer-reviewed journal.
(ma2024dnajb1prkacafusionproteinregulated pages 1-4): Rosanna K. Ma, Pei-Yin Tsai, Alaa R. Farghli, Alexandria Shumway, Matt Kanke, John D. Gordan, Taranjit S. Gujral, Khashayar Vakili, Manabu Nukaya, Leila Noetzli, Sean Ronnekleiv-Kelly, Wendy Broom, Joeva Barrow, and Praveen Sethupathy. Dnajb1-prkaca fusion protein-regulated linc00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma. PLOS Genetics, Jun 2024. URL: https://doi.org/10.1101/2023.06.02.543290, doi:10.1101/2023.06.02.543290. This article has 14 citations and is from a domain leading peer-reviewed journal.
(kirk2024dnajb1prkacafusionneoantigens pages 1-3): Allison M. Kirk, Jeremy Chase Crawford, Ching-Heng Chou, Cliff Guy, Kirti Pandey, Tanya Kozlik, Ravi K. Shah, Shanzou Chung, Phuong Nguyen, Xiaoyu Zhang, Jin Wang, Matthew Bell, Robert C. Mettelman, E. Kaitlynn Allen, Mikhail V. Pogorelyy, Hyunjin Kim, Anastasia A. Minervina, Walid Awad, Resha Bajracharya, Toni White, Donald Long, Brittney Gordon, Michelle Morrison, Evan S. Glazer, Andrew J. Murphy, Yixing Jiang, Elizabeth A. Fitzpatrick, Mark Yarchoan, Praveen Sethupathy, Nathan P. Croft, Anthony W. Purcell, Sara M. Federico, Elizabeth Stewart, Stephen Gottschalk, Anthony E. Zamora, Christopher DeRenzo, Scott E. Strome, and Paul G. Thomas. Dnajb1-prkaca fusion neoantigens elicit rare endogenous t cell responses that potentiate cell therapy for fibrolamellar carcinoma. Cell Reports Medicine, 5:101469, Mar 2024. URL: https://doi.org/10.1016/j.xcrm.2024.101469, doi:10.1016/j.xcrm.2024.101469. This article has 14 citations and is from a peer-reviewed journal.
(hackenbruch2024fusionvac2201aphase pages 11-11): Christopher Hackenbruch, Jens Bauer, Jonas S. Heitmann, Yacine Maringer, Annika Nelde, Monika Denk, Lisa Zieschang, Christine Kammer, Birgit Federmann, Susanne Jung, Peter Martus, Nisar P. Malek, Konstantin Nikolaou, Helmut R. Salih, Michael Bitzer, and Juliane S. Walz. Fusionvac22_01: a phase i clinical trial evaluating a dnajb1-prkaca fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion. Frontiers in Oncology, Mar 2024. URL: https://doi.org/10.3389/fonc.2024.1367450, doi:10.3389/fonc.2024.1367450. This article has 11 citations.
(hackenbruch2024fusionvac2201aphase pages 1-2): Christopher Hackenbruch, Jens Bauer, Jonas S. Heitmann, Yacine Maringer, Annika Nelde, Monika Denk, Lisa Zieschang, Christine Kammer, Birgit Federmann, Susanne Jung, Peter Martus, Nisar P. Malek, Konstantin Nikolaou, Helmut R. Salih, Michael Bitzer, and Juliane S. Walz. Fusionvac22_01: a phase i clinical trial evaluating a dnajb1-prkaca fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion. Frontiers in Oncology, Mar 2024. URL: https://doi.org/10.3389/fonc.2024.1367450, doi:10.3389/fonc.2024.1367450. This article has 11 citations.
(hackenbruch2024fusionvac2201aphase pages 7-8): Christopher Hackenbruch, Jens Bauer, Jonas S. Heitmann, Yacine Maringer, Annika Nelde, Monika Denk, Lisa Zieschang, Christine Kammer, Birgit Federmann, Susanne Jung, Peter Martus, Nisar P. Malek, Konstantin Nikolaou, Helmut R. Salih, Michael Bitzer, and Juliane S. Walz. Fusionvac22_01: a phase i clinical trial evaluating a dnajb1-prkaca fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion. Frontiers in Oncology, Mar 2024. URL: https://doi.org/10.3389/fonc.2024.1367450, doi:10.3389/fonc.2024.1367450. This article has 11 citations.
(neumayer2024galnacconjugatedsirnatargeting pages 1-2): Christoph Neumayer, Denise Ng, David Requena, Caroline S. Jiang, Adam Qureshi, Roger Vaughan, Thazha P. Prakash, Alexey Revenko, and Sanford M. Simon. Galnac-conjugated sirna targeting the dnajb1-prkaca fusion junction in fibrolamellar hepatocellular carcinoma. Molecular Therapy, 32:140-151, Jan 2024. URL: https://doi.org/10.1016/j.ymthe.2023.11.012, doi:10.1016/j.ymthe.2023.11.012. This article has 16 citations and is from a highest quality peer-reviewed journal.

Citations

zhang2023jdomainproteinchaperone pages 3-4
zhang2023jdomainproteinchaperone pages 4-6
zhang2023jdomainproteinchaperone pages 8-9
neumayer2024galnacconjugatedsirnatargeting pages 1-2
song2024modelsoffibrolamellar pages 1-2
zhang2023jdomainproteinchaperone pages 13-14
zhang2023jdomainproteinchaperone pages 28-32
requena2024livercancermultiomics pages 1-2
requena2024livercancermultiomics pages 2-3
https://doi.org/10.1016/j.tcb.2022.05.004
https://doi.org/10.3390/ijms222413527
https://doi.org/10.3389/fimmu.2024.1459942
https://doi.org/10.1038/s41467-024-55238-2
https://doi.org/10.1101/2023.06.02.543290
https://doi.org/10.1016/j.xcrm.2024.101469
https://doi.org/10.1016/j.ymthe.2023.11.012
https://doi.org/10.3389/fonc.2024.1367450
https://doi.org/10.3390/ijms222413527,
https://doi.org/10.1016/j.tcb.2022.05.004,
https://doi.org/10.3389/fimmu.2024.1459942,
https://doi.org/10.1038/s41467-024-55238-2,
https://doi.org/10.1101/2023.06.02.543290,
https://doi.org/10.1016/j.xcrm.2024.101469,
https://doi.org/10.3389/fonc.2024.1367450,
https://doi.org/10.1016/j.ymthe.2023.11.012,

📄 View Raw YAML

id: P25685
gene_symbol: DNAJB1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  DNAJB1 (also known as HSP40, HDJ1) is a class II (class B) J-domain protein that
  functions as a co-chaperone for HSP70 family members. Its domain architecture comprises
  an N-terminal J-domain (with conserved HPD motif), a glycine/phenylalanine-rich (G/F)
  region, and C-terminal beta-sandwich client-binding domains (CTD-I and CTD-II) plus a
  dimerization domain; notably, class B JDPs lack the zinc-finger-like region present in
  class A members (DOI:10.1016/j.tcb.2022.05.004). DNAJB1 stimulates the ATPase activity
  of HSP70 and delivers substrates to the HSP70 chaperone machinery, promoting protein
  folding (foldase-type activity). A key regulatory mechanism is G/F-mediated
  autoinhibition of the J-domain, which is relieved by a secondary contact between the
  Hsp70 C-terminal EEVD motif and a positively charged groove in DNAJB1 CTD-I, enabling
  productive Hsp70 engagement (DOI:10.1016/j.tcb.2022.05.004). Beyond simple refolding,
  DNAJB1 participates in JDP scaffolding and hetero-oligomerization to create potent
  Hsp70-based disaggregases, remaining associated with aggregates to recruit multiple
  Hsp70 molecules (DOI:10.1016/j.tcb.2022.05.004). DNAJB1 also negatively regulates
  HSF1 transcriptional activity during the attenuation phase of the heat shock response
  by binding HSF1 in complex with HSP70. It can modulate the p53/MDM2 axis by binding
  and stabilizing MDM2 and destabilizing PDCD5, with context-dependent effects on p53
  signaling (DOI:10.3390/ijms222413527). DNAJB1 is stress-inducible and translocates
  from the cytoplasm to the nucleus and nucleolus upon heat shock. Notably, the
  DNAJB1-PRKACA gene fusion drives fibrolamellar carcinoma and is a distinct chimeric
  oncoprotein that should not be conflated with wild-type DNAJB1 co-chaperone function.
alternative_products:
- name: '1'
  id: P25685-1
- name: '2'
  id: P25685-2
  sequence_note: VSP_056414
existing_annotations:
# ===== IBA annotations (phylogenetic) =====
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      DNAJB1 is a class II J-domain co-chaperone that promotes protein folding through the
      HSP70 chaperone machinery. Rauch and Gestwicki (PMID:24318877) showed that combinations
      of J proteins including DnaJB1 with NEFs and HSP70 produce potent chaperone activities
      in luciferase refolding assays. Hageman et al. (PMID:21231916) showed that DNAJB1
      supports luciferase refolding when paired with HSP70, classifying it as a foldase-type
      co-chaperone. The IBA annotation for protein folding is well supported by phylogenetic
      inference and experimental data.
    action: ACCEPT
    reason: >-
      Protein folding is the core biological process of DNAJB1. As a class II J-domain
      co-chaperone, DNAJB1 delivers substrates to HSP70 and stimulates the ATPase-dependent
      folding cycle (PMID:24318877, PMID:21231916). This IBA annotation is consistent with
      extensive experimental evidence and phylogenetic conservation.
    supported_by:
    - reference_id: PMID:24318877
      supporting_text: >-
        we combined the Hsp70-NEF pairs with cochaperones of the J protein family (DnaJA1,
        DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The activity of the
        combinations in ATPase and luciferase refolding assays were dependent on the
        identity and stoichiometry of both the J protein and NEF
    - reference_id: PMID:21231916
      supporting_text: >-
        chaperones that supported luciferase refolding were poor suppressors of polyQ
        aggregation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      DNAJB1 is primarily a cytosolic protein. Hageman et al. (PMID:21231916) stated that
      most HSP70/HSPA and HSP40/DNAJ proteins are localized in the cytosol. UniProt confirms
      cytoplasmic localization. The IBA annotation for cytosol is well supported.
    action: ACCEPT
    reason: >-
      Cytosol is the primary localization of DNAJB1 under normal conditions, consistent
      with its role as a cytosolic co-chaperone for HSP70. Phylogenetic inference and
      direct experimental evidence (immunofluorescence, PMID:21231916) support this.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding
        genes and most of the corresponding proteins are localized in the cytosol.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      DNAJB1 negatively regulates HSF1-driven transcription during the attenuation phase
      of the heat shock response. Shi et al. (PMID:9499401) demonstrated that Hsp70 and
      the cochaperone Hdj1 (DNAJB1) interact directly with the transactivation domain of
      HSF1 and repress heat shock gene transcription. The IBA annotation is well supported.
    action: KEEP_AS_NON_CORE
    reason: >-
      While experimentally validated (PMID:9499401), negative regulation of transcription
      is not a core molecular function of DNAJB1 but rather a downstream consequence of
      its co-chaperone activity in the HSP70 complex. DNAJB1 represses HSF1 transcription
      as part of the heat shock attenuation mechanism, which is a secondary regulatory
      role. The IBA annotation is phylogenetically sound.
    supported_by:
    - reference_id: PMID:9499401
      supporting_text: >-
        the molecular chaperone Hsp70 and the cochaperone Hdj1 interact directly with the
        transactivation domain of HSF1 and repress heat shock gene transcription.
- term:
    id: GO:0003714
    label: transcription corepressor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      Shi et al. (PMID:9499401) showed that overexpression of Hdj1 (DNAJB1) represses the
      transcriptional activity of HSF1, including a transfected GAL4-HSF1 activation domain
      fusion protein. This demonstrates transcription corepressor activity. The IBA annotation
      is phylogenetically consistent.
    action: KEEP_AS_NON_CORE
    reason: >-
      Transcription corepressor activity is a real but non-core function of DNAJB1. It acts
      as a corepressor specifically in the context of HSF1-mediated heat shock gene
      transcription, working together with HSP70 to repress the HSF1 transactivation domain
      (PMID:9499401). This is a secondary regulatory role dependent on its primary
      co-chaperone activity, not a general transcription corepressor function.
    supported_by:
    - reference_id: PMID:9499401
      supporting_text: >-
        Overexpression of either chaperone represses the transcriptional activity of a
        transfected GAL4-HSF1 activation domain fusion protein and endogenous HSF1.
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      DNAJB1 is a J-domain co-chaperone that physically binds HSP70 family members through
      its J-domain. UniProt records interactions with HSP70/HSPA1A (PMID:14503850) and
      this is a defining feature of all J-domain proteins. The IBA annotation accurately
      reflects the core molecular function of DNAJB1.
    action: ACCEPT
    reason: >-
      HSP70 binding via the J-domain is the core molecular function of DNAJB1 as a
      J-domain co-chaperone. This is the defining feature of the DnaJ family and is
      essential for DNAJB1's ability to stimulate HSP70 ATPase activity and deliver
      substrates. Phylogenetically well-conserved and experimentally validated.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962).
      DNAJB1 is a class II J-domain protein that functions as a foldase-type co-chaperone
      for HSP70, not as an independent holdase. Hageman et al. (PMID:21231916) showed that
      DNAJB1 promotes efficient luciferase refolding when paired with HSP70, placing it in
      the foldase category. UniProt describes DNAJB1 as stimulating ATP hydrolysis and the
      folding of unfolded proteins mediated by HSPA1A/B. The correct replacement term is
      GO:0044183 (protein folding chaperone), which accurately describes DNAJB1's role in
      binding to proteins to assist the protein folding process as part of the HSP70
      chaperone machinery.
    action: MODIFY
    reason: >-
      GO:0051082 is scheduled for obsoletion. The obsolescence notice (go-ontology#30962)
      specifies that annotations should be migrated to either holdase chaperone activity
      or GO:0044183 (protein folding chaperone, i.e. foldase). DNAJB1 is definitively a
      foldase-type co-chaperone, not a holdase. Hageman et al. (PMID:21231916) demonstrated
      that chaperones supporting luciferase refolding (foldase activity) were poor suppressors
      of polyQ aggregation (holdase activity), and vice versa. DNAJB1 promotes refolding
      when paired with HSP70, classifying it as a foldase. This IBA annotation by phylogenetic
      inference correctly identified the general chaperone activity of DNAJB1, but the term
      needs updating to GO:0044183 to reflect the foldase function and the obsolescence of
      GO:0051082.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:21231916
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        Overexpressed chaperones that suppressed polyQ aggregation were found not to be
        able to stimulate luciferase refolding. Inversely, chaperones that supported
        luciferase refolding were poor suppressors of polyQ aggregation.
# ===== IEA annotations (electronic) =====
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      DNAJB1 translocates from the cytoplasm to the nucleus upon heat shock. UniProt
      subcellular location annotation confirms nuclear localization under stress conditions,
      supported by Hattori et al. (PubMed:1586970). This IEA annotation from UniProtKB
      subcellular location vocabulary mapping is consistent with known biology.
    action: ACCEPT
    reason: >-
      Nuclear localization of DNAJB1 upon heat shock is well-documented. UniProt states
      that DNAJB1 translocates rapidly from the cytoplasm to the nucleus upon heat shock.
      The IEA mapping from UniProt subcellular location is appropriate.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      DNAJB1 translocates to the nucleolus upon heat shock. UniProt subcellular location
      confirms nucleolar localization under stress, supported by Hattori et al.
      (PubMed:1586970). The IEA annotation is consistent with known stress-induced
      translocation behavior.
    action: ACCEPT
    reason: >-
      Nucleolar localization of DNAJB1 upon heat shock is documented in UniProt based
      on Hattori et al. The IEA mapping from UniProt subcellular location vocabulary is
      appropriate. DNAJB1 translocates to the nucleolus under heat shock stress.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      DNAJB1 is primarily cytoplasmic under normal conditions. UniProt subcellular location
      lists cytoplasm as a primary location. This is broader than the cytosol annotation
      but acceptable as an IEA annotation.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization of DNAJB1 is well-established. While the cytosol annotation
      is more specific, cytoplasm is a valid broader term from the UniProt mapping. Both
      are correct.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Protein folding is a core process for DNAJB1 as a J-domain co-chaperone. This IEA
      annotation from combined automated methods is consistent with the IBA annotation
      and experimental evidence.
    action: ACCEPT
    reason: >-
      Redundant with the IBA annotation for the same term, but the IEA is independently
      valid. Protein folding is a core function of DNAJB1 through its HSP70 co-chaperone
      activity.
- term:
    id: GO:0006986
    label: response to unfolded protein
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      DNAJB1 is a heat shock-inducible co-chaperone that participates in the cellular
      response to unfolded proteins. As a J-domain protein that delivers substrates to
      HSP70, it is involved in the response to unfolded protein. This IEA annotation from
      ARBA machine learning is reasonable.
    action: ACCEPT
    reason: >-
      DNAJB1 is indeed involved in the response to unfolded protein as a heat shock-inducible
      J-domain co-chaperone. While the term is broad, it is appropriate for an IEA annotation.
      It is consistent with the TAS annotation for the same term (PMID:8975727).
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962). This
      IEA annotation was inferred from the InterPro domain IPR008971 (HSP40/DnaJ
      peptide-binding domain) mapping to GO:0051082. While the DnaJ peptide-binding domain
      does indeed interact with substrates, the function of DNAJB1 is best described as
      protein folding chaperone activity (GO:0044183), as DNAJB1 acts as a foldase-type
      co-chaperone for HSP70. DNAJB1 does not independently hold unfolded proteins; it
      delivers substrates to HSP70 and stimulates the ATPase-dependent folding cycle.
    action: MODIFY
    reason: >-
      GO:0051082 is scheduled for obsoletion (go-ontology#30962). This IEA annotation
      derives from the InterPro domain mapping (IPR008971, HSP40/DnaJ peptide-binding
      domain). The InterPro2GO mapping will need to be updated when GO:0051082 is
      obsoleted. For DNAJB1 specifically, the correct replacement is GO:0044183 (protein
      folding chaperone), since DNAJB1 is a foldase-type J-domain protein that promotes
      protein refolding in concert with HSP70 (PMID:21231916).
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:21231916
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        Overexpressed chaperones that suppressed polyQ aggregation were found not to be
        able to stimulate luciferase refolding. Inversely, chaperones that supported
        luciferase refolding were poor suppressors of polyQ aggregation.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      DNAJB1 binds HSP70 family members (protein-folding chaperones) through its J-domain.
      This IEA annotation from ARBA machine learning is consistent with the known interaction
      between DNAJB1 and HSP70 chaperones (PMID:9499401, PMID:24318877).
    action: ACCEPT
    reason: >-
      DNAJB1 is a co-chaperone that physically binds protein-folding chaperones (HSP70
      family members). This IEA annotation is appropriate and consistent with the more
      specific Hsp70 protein binding annotation.
# ===== Protein binding (IPI) annotations =====
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17024176
  review:
    summary: >-
      Hayashida et al. (PMID:17024176) studied a novel HSF1-mediated death pathway
      suppressed by heat shock proteins. The paper reports that Hsps bound directly to the
      N-terminal pleckstrin-homology like domain of Tdag51 and suppressed death activity.
      DNAJB1 binding was detected in this context.
    action: REMOVE
    reason: >-
      Protein binding is uninformative as a GO annotation. The interaction described in
      PMID:17024176 between HSPs and Tdag51 is tangential to DNAJB1 core function. More
      specific terms such as Hsp70 protein binding or protein-folding chaperone binding
      already capture the meaningful interactions of DNAJB1.
    supported_by:
    - reference_id: PMID:17024176
      supporting_text: >-
        Hsps bound directly to the N-terminal pleckstrin-homology like (PHL) domain of
        Tdag51, and suppressed death activity of the C-terminal
        proline/glutamine/histidine-rich domain.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21044950
  review:
    summary: >-
      PMID:21044950 is a genome-wide YFP fluorescence complementation screen for telomere
      signaling regulators. This is a large-scale screen and the protein binding annotation
      is uninformative.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. This large-scale screen result does not provide
      specific functional insight into DNAJB1's molecular function. More informative MF
      terms such as Hsp70 protein binding already exist.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21163940
  review:
    summary: >-
      PMID:21163940 is an interactome mapping study related to Alzheimer's disease. The
      protein binding annotation from this large-scale study is uninformative.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. Large-scale interactome mapping does not provide
      specific functional insight for DNAJB1 curation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  review:
    summary: >-
      PMID:25036637 describes a quantitative chaperone interaction network. While relevant
      to understanding DNAJB1 as a chaperone, the protein binding annotation is uninformative.
      The interactions are better captured by Hsp70 protein binding and protein-folding
      chaperone binding terms.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. The chaperone interaction network data is better
      captured by the more specific Hsp70 protein binding and protein-folding chaperone
      binding annotations already present.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27173435
  review:
    summary: >-
      PMID:27173435 describes an organelle-specific protein landscape. The protein binding
      annotation is uninformative for DNAJB1 curation.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. Large-scale proteomics does not provide specific
      functional insight for DNAJB1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: >-
      PMID:28514442 describes architecture of the human interactome. The protein binding
      annotation from this large-scale interactome study is uninformative.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. Large-scale interactome mapping does not provide
      specific functional insight for DNAJB1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      PMID:32296183 is a reference map of the human binary protein interactome. The protein
      binding annotation is uninformative.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. Large-scale interactome mapping does not provide
      specific functional insight for DNAJB1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: >-
      PMID:32814053 is an interactome mapping study of neurodegenerative disease proteins.
      The protein binding annotation is uninformative.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. Interactome mapping for neurodegenerative disease
      does not provide specific functional insight for DNAJB1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      PMID:33961781 describes dual proteome-scale networks of the human interactome. The
      protein binding annotation is uninformative.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. Large-scale interactome mapping does not provide
      specific functional insight for DNAJB1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  review:
    summary: >-
      PMID:35271311 (OpenCell) is an endogenous tagging study for cellular organization
      cartography. The protein binding annotation is uninformative.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. Large-scale cellular organization studies do not
      provide specific functional insight for DNAJB1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36931259
  review:
    summary: >-
      PMID:36931259 describes a chaperone-like role for 14-3-3 proteins. The protein
      binding annotation is uninformative.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. The interaction with 14-3-3 proteins may be
      interesting but the generic protein binding term does not capture any specific
      functional relationship.
# ===== Ensembl Compara IEA annotations (GO_REF:0000107) =====
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      This IEA annotation was transferred from an ortholog by Ensembl Compara. DNAJB1 is
      a ubiquitous co-chaperone without specific synaptic function. While chaperones may
      be present at the postsynaptic density for proteostasis, there is no evidence that
      postsynaptic density is a primary or functionally significant localization for DNAJB1.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      DNAJB1 is a ubiquitously expressed co-chaperone. Its presence at the postsynaptic
      density likely reflects general proteostasis rather than a specific synaptic function.
      This ortholog transfer may over-annotate a non-specific localization.
- term:
    id: GO:0030900
    label: forebrain development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      This IEA annotation was transferred from an ortholog by Ensembl Compara. DNAJB1 is
      a ubiquitous co-chaperone, and there is no specific evidence linking it to forebrain
      development as a core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      DNAJB1 is ubiquitously expressed and functions as a general co-chaperone for HSP70.
      Forebrain development likely reflects pleiotropic developmental consequences of general
      protein folding activity rather than a specific role for DNAJB1 in forebrain
      development. This is likely an over-annotation from ortholog transfer.
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      This IEA annotation was transferred from an ortholog by Ensembl Compara. DNAJB1 is
      a ubiquitous cytosolic co-chaperone. Its presence in neuronal cell bodies reflects
      general cytoplasmic/cytosolic localization rather than specific neuronal enrichment.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      DNAJB1 is ubiquitously expressed. Neuronal cell body localization likely reflects
      general cytosolic presence rather than specific neuronal targeting. This is an
      over-annotation from ortholog transfer.
- term:
    id: GO:0043197
    label: dendritic spine
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      This IEA annotation was transferred from an ortholog by Ensembl Compara. DNAJB1 is
      a ubiquitous co-chaperone without known specific dendritic spine function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      DNAJB1 is a ubiquitous co-chaperone. Dendritic spine localization from ortholog
      transfer likely represents general proteostasis rather than specific synaptic function.
      This is an over-annotation.
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      DNAJB1 functions as a protein folding chaperone (foldase-type) as part of the HSP70
      machinery. Hageman et al. (PMID:21231916) demonstrated that DNAJB1 supports luciferase
      refolding when paired with HSP70. This IEA annotation from Ensembl Compara ortholog
      transfer is accurate.
    action: ACCEPT
    reason: >-
      Protein folding chaperone is the correct MF term for DNAJB1 as a foldase-type
      J-domain co-chaperone. This is consistent with the proposed replacement for the
      obsolete GO:0051082 annotations and accurately reflects DNAJB1 core function.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        Overexpressed chaperones that suppressed polyQ aggregation were found not to be
        able to stimulate luciferase refolding. Inversely, chaperones that supported
        luciferase refolding were poor suppressors of polyQ aggregation.
- term:
    id: GO:0061827
    label: sperm head
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      This IEA annotation was transferred from an ortholog by Ensembl Compara. While
      PMID:21630459 (HDA) independently identifies DNAJB1 in the sperm nucleus proteome,
      sperm head localization is likely a reflection of general chaperone presence rather
      than specific function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Sperm head localization is not a core annotation for DNAJB1 but is supported by
      independent proteomic evidence (PMID:21630459, HDA for nucleus). Chaperones are
      expected to be present in spermatozoa for proteostasis. Keep as non-core.
- term:
    id: GO:0098794
    label: postsynapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      This IEA annotation was transferred from an ortholog by Ensembl Compara. DNAJB1 is
      a ubiquitous co-chaperone; postsynaptic localization is not specific to DNAJB1.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      DNAJB1 is ubiquitously expressed. Postsynapse localization from ortholog transfer
      likely represents general proteostasis presence rather than specific synaptic
      function. Over-annotation.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      This IEA annotation was transferred from an ortholog by Ensembl Compara. DNAJB1 is
      a ubiquitous co-chaperone without known specific glutamatergic synapse function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      DNAJB1 is ubiquitously expressed. Glutamatergic synapse localization from ortholog
      transfer likely represents general proteostasis rather than specific synaptic function.
      Over-annotation.
# ===== IDA annotations from HPA immunofluorescence (GO_REF:0000052) =====
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      DNAJB1 is detected in the nucleoplasm by HPA immunofluorescence (GO_REF:0000052).
      This is consistent with the known translocation of DNAJB1 to the nucleus upon heat
      shock (UniProt) and its role in HSF1 regulation in the nucleus (PMID:9499401).
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is consistent with DNAJB1's known nuclear translocation
      under stress and its role in repressing HSF1 transcriptional activity in the nucleus.
      HPA immunofluorescence data provides direct evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      DNAJB1 is detected in the cytosol by HPA immunofluorescence (GO_REF:0000052).
      Consistent with its primary cytosolic localization and role as a cytosolic co-chaperone
      for HSP70.
    action: ACCEPT
    reason: >-
      Cytosol is the primary localization of DNAJB1 under normal conditions. HPA
      immunofluorescence confirms this well-established localization.
# ===== Reactome TAS annotation =====
- term:
    id: GO:1900034
    label: regulation of cellular response to heat
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371453
  review:
    summary: >-
      Reactome R-HSA-3371453 models the regulation of HSF1-mediated heat shock response.
      DNAJB1 participates in this pathway by repressing HSF1 transcriptional activity
      together with HSP70 during the attenuation phase (PMID:9499401).
    action: ACCEPT
    reason: >-
      DNAJB1 is a key regulator of the cellular response to heat. It participates in the
      attenuation of the HSF1-mediated heat shock response by binding HSF1 with HSP70 and
      repressing transcription (PMID:9499401, Reactome:R-HSA-5082384). This is a well-
      supported annotation.
# ===== IDA annotations from specific publications =====
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IDA
  original_reference_id: PMID:23921388
  review:
    summary: >-
      Jakobsson et al. (PMID:23921388) characterized METTL21A methyltransferase and its
      effects on HSP70. The paper mentions that J-proteins stimulate intrinsic ATPase
      activity of HSP70s, consistent with DNAJB1 function. However, this paper primarily
      studies METTL21A, not DNAJB1 directly.
    action: ACCEPT
    reason: >-
      ATPase activator activity is a core molecular function of DNAJB1. As a J-domain
      co-chaperone, DNAJB1 stimulates the intrinsic ATPase activity of HSP70 family members.
      While PMID:23921388 focuses on METTL21A, DNAJB1 ATPase activation is extensively
      documented (PMID:24318877, Reactome:R-HSA-5251959). Multiple independent lines of
      evidence support this annotation.
    supported_by:
    - reference_id: PMID:23921388
      supporting_text: >-
        Hsp70 proteins constitute an evolutionarily conserved protein family of
        ATP-dependent molecular chaperones involved in a wide range of biological
        processes.
- term:
    id: GO:1903334
    label: positive regulation of protein folding
  evidence_type: IDA
  original_reference_id: PMID:23921388
  review:
    summary: >-
      Jakobsson et al. (PMID:23921388) studied methylation effects on HSP70 chaperone
      function. DNAJB1 positively regulates protein folding by stimulating HSP70 ATPase
      activity and promoting the HSP70 folding cycle. This is consistent with DNAJB1's
      well-established foldase co-chaperone role.
    action: ACCEPT
    reason: >-
      Positive regulation of protein folding accurately describes DNAJB1's role as a
      co-chaperone that stimulates HSP70-mediated folding. This is a core function.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:9499401
  review:
    summary: >-
      Shi et al. (PMID:9499401) directly demonstrated that Hdj1 (DNAJB1) interacts with
      the transactivation domain of HSF1 and represses heat shock gene transcription.
      Overexpression of DNAJB1 represses HSF1-driven transcription.
    action: KEEP_AS_NON_CORE
    reason: >-
      Directly demonstrated by Shi et al. (PMID:9499401) using overexpression of Hdj1
      repressing GAL4-HSF1 activation domain fusion and endogenous HSF1. While
      experimentally valid, this transcriptional repression is specific to the heat shock
      attenuation context and is a secondary consequence of co-chaperone activity, not
      a core function.
    supported_by:
    - reference_id: PMID:9499401
      supporting_text: >-
        Overexpression of either chaperone represses the transcriptional activity of a
        transfected GAL4-HSF1 activation domain fusion protein and endogenous HSF1.
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IDA
  original_reference_id: PMID:9499401
  review:
    summary: >-
      Shi et al. (PMID:9499401) demonstrated that DNAJB1 (Hdj1) participates in the cellular
      response to heat by interacting with HSF1 during the attenuation phase of the heat shock
      response. The heat shock response involves DNAJB1 acting with HSP70 to repress HSF1
      transcriptional activity.
    action: ACCEPT
    reason: >-
      DNAJB1 is heat shock-inducible and plays a direct role in the cellular response to heat
      by participating in the attenuation of HSF1-mediated transcription (PMID:9499401). This
      is well-supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:9499401
      supporting_text: >-
        the molecular chaperone Hsp70 and the cochaperone Hdj1 interact directly with the
        transactivation domain of HSF1 and repress heat shock gene transcription.
- term:
    id: GO:0140416
    label: transcription regulator inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:9499401
  review:
    summary: >-
      Shi et al. (PMID:9499401) showed that DNAJB1 (Hdj1) directly inhibits HSF1
      transcriptional activity by binding to the HSF1 transactivation domain. This
      constitutes transcription regulator inhibitor activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      DNAJB1 inhibits HSF1 transcriptional activity during heat shock attenuation
      (PMID:9499401). While the annotation is accurate, this is not a core molecular
      function of DNAJB1 but rather a specialized regulatory activity in the HSF1 heat
      shock response pathway. Its primary role is as a co-chaperone for HSP70.
    supported_by:
    - reference_id: PMID:9499401
      supporting_text: >-
        the molecular chaperone Hsp70 and the cochaperone Hdj1 interact directly with the
        transactivation domain of HSF1 and repress heat shock gene transcription.
# ===== Reactome TAS annotations for ATPase activator activity =====
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5251955
  review:
    summary: >-
      Reactome R-HSA-5251955 models HSP40s activating intrinsic ATPase activity of HSP70s
      in the nucleoplasm. DNAJB1 translocates to the nucleus under heat shock and activates
      HSP70 ATPase activity there.
    action: ACCEPT
    reason: >-
      ATPase activator activity is a core molecular function of DNAJB1. The Reactome
      annotation for nucleoplasmic ATPase activation is consistent with DNAJB1's known
      nuclear translocation under heat shock and its ability to stimulate HSP70 ATPase.
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5251959
  review:
    summary: >-
      Reactome R-HSA-5251959 models HSP40s activating intrinsic ATPase activity of HSP70s
      in the cytosol. DNAJB1 is explicitly listed as one of the HSP40s that modulates
      intrinsic ATPase activity of HSP70s.
    action: ACCEPT
    reason: >-
      ATPase activator activity in the cytosol is a core function of DNAJB1. The Reactome
      pathway explicitly lists DNAJB1 as an HSP40 that activates HSP70 ATPase activity.
# ===== HDA and other annotations =====
- term:
    id: GO:0045296
    label: cadherin binding
  evidence_type: HDA
  original_reference_id: PMID:25468996
  review:
    summary: >-
      PMID:25468996 describes an E-cadherin interactome study using quantitative proteomics.
      DNAJB1 was identified in the cadherin interactome by high-throughput proteomics. This
      is likely a non-specific interaction due to DNAJB1's general chaperone activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Cadherin binding is not a known or expected function of DNAJB1. As a general
      co-chaperone, DNAJB1 may associate with many cellular protein complexes for
      proteostasis without specific binding activity. The HDA evidence from a proteomics
      screen is not sufficient to establish specific cadherin binding as a function.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:21231916
  review:
    summary: >-
      Hageman et al. (PMID:21231916) systematically assessed functional differences among
      HSP70/HSPA and HSP40/DNAJ family members. DNAJB1 was shown to interact with and
      modulate HSP70 chaperone activity, directly demonstrating protein-folding chaperone
      binding.
    action: ACCEPT
    reason: >-
      DNAJB1 binds HSP70 chaperones through its J-domain, which is central to its function.
      PMID:21231916 provides direct evidence of functional DNAJB1-HSP70 interaction in
      luciferase refolding and polyQ aggregation assays.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding
        genes and most of the corresponding proteins are localized in the cytosol. To
        test for possible functional differences and/or substrate specificity, we
        assessed the effect of overexpression of each of these HSPs on refolding of
        heat-denatured luciferase and on the suppression of aggregation of a
        non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment.
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IDA
  original_reference_id: PMID:24318877
  review:
    summary: >-
      Rauch and Gestwicki (PMID:24318877) combined Hsp70-NEF pairs with J proteins including
      DnaJB1 and measured ATPase and luciferase refolding activities. DNAJB1 was directly
      shown to stimulate HSP70 ATPase activity in these in vitro assays.
    action: ACCEPT
    reason: >-
      ATPase activator activity is a core molecular function of DNAJB1. PMID:24318877
      provides direct biochemical evidence of DNAJB1 stimulating HSP70 ATPase activity
      in vitro.
    supported_by:
    - reference_id: PMID:24318877
      supporting_text: >-
        we combined the Hsp70-NEF pairs with cochaperones of the J protein family (DnaJA1,
        DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The activity of the
        combinations in ATPase and luciferase refolding assays were dependent on the
        identity and stoichiometry of both the J protein and NEF
- term:
    id: GO:0003714
    label: transcription corepressor activity
  evidence_type: IDA
  original_reference_id: PMID:9499401
  review:
    summary: >-
      Shi et al. (PMID:9499401) demonstrated that Hdj1 (DNAJB1) represses HSF1
      transcriptional activity. Overexpression of DNAJB1 represses both GAL4-HSF1 fusion
      and endogenous HSF1, functioning as a transcription corepressor in the heat shock
      response context.
    action: KEEP_AS_NON_CORE
    reason: >-
      The IDA evidence from PMID:9499401 directly demonstrates corepressor activity on
      HSF1. This is a duplicate of the IBA annotation for the same term, both supported
      by the same mechanism. Keep as non-core since transcription corepression is secondary
      to the primary co-chaperone function.
    supported_by:
    - reference_id: PMID:9499401
      supporting_text: >-
        Overexpression of either chaperone represses the transcriptional activity of a
        transfected GAL4-HSF1 activation domain fusion protein and endogenous HSF1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9499401
  review:
    summary: >-
      Shi et al. (PMID:9499401) showed that Hdj1 (DNAJB1) interacts directly with the
      transactivation domain of HSF1. This interaction is real but better described by
      more specific terms (transcription regulator inhibitor activity, protein-folding
      chaperone binding).
    action: REMOVE
    reason: >-
      Protein binding is uninformative. The specific interaction with HSF1 described in
      PMID:9499401 is already captured by the transcription regulator inhibitor activity
      and transcription corepressor activity annotations. The generic protein binding term
      adds no additional information.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27120771
  review:
    summary: >-
      PMID:27120771 concerns MAGED2 mutations and Bartter's syndrome. The paper mentions
      interaction with a cytoplasmic heat-shock protein but DNAJB1 is not the focus. This
      protein binding annotation is tangential to DNAJB1 function.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. PMID:27120771 is primarily about MAGED2 and
      Bartter's syndrome. Any interaction with DNAJB1 described here is tangential and
      the generic protein binding term adds no useful information about DNAJB1 function.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:25468996
  review:
    summary: >-
      PMID:25468996 is an E-cadherin interactome study. DNAJB1 being detected in the
      cytoplasm is consistent with its known primary cytoplasmic localization. However,
      the IDA evidence code from a proteomics study is appropriate.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization of DNAJB1 is well-established and consistent with UniProt
      subcellular location data. Acceptable as independent confirmation.
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IDA
  original_reference_id: PMID:20060297
  review:
    summary: >-
      Arndt et al. (PMID:20060297) described chaperone-assisted selective autophagy (CASA)
      for muscle maintenance. The paper focuses on BAG-3 coordinating Hsc70 and HspB8 during
      degradation of damaged Z disk components. DNAJB1 ATPase activator activity may be
      referenced in the context of the HSP70 chaperone cycle but this paper primarily studies
      the BAG3/CASA pathway.
    action: ACCEPT
    reason: >-
      ATPase activator activity is a core function of DNAJB1. While PMID:20060297 focuses
      on CASA, DNAJB1's role in activating HSP70 ATPase is well-established across multiple
      independent studies (PMID:24318877, PMID:23921388, Reactome). The annotation is
      valid regardless of the specific reference context.
    supported_by:
    - reference_id: PMID:20060297
      supporting_text: >-
        Stv and its mammalian ortholog BAG-3 coordinate the activity of Hsc70 and the
        small heat shock protein HspB8 during disposal that is initiated by the
        chaperone-associated ubiquitin ligase CHIP and the autophagic ubiquitin adaptor p62.
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: IPI
  original_reference_id: PMID:23921388
  review:
    summary: >-
      Jakobsson et al. (PMID:23921388) studied METTL21A methyltransferase effects on HSP70.
      The study demonstrates DNAJB1 interaction with HSP70 family members in the context
      of methylation modulation of chaperone function. HSP70 binding is a core interaction
      for DNAJB1.
    action: ACCEPT
    reason: >-
      Hsp70 protein binding is a core molecular function of DNAJB1 as a J-domain
      co-chaperone. The J-domain of DNAJB1 directly binds HSP70 to stimulate ATPase
      activity. This annotation is well-supported by multiple studies.
    supported_by:
    - reference_id: PMID:23921388
      supporting_text: >-
        Hsp70 proteins constitute an evolutionarily conserved protein family of
        ATP-dependent molecular chaperones involved in a wide range of biological
        processes.
- term:
    id: GO:0051117
    label: ATPase binding
  evidence_type: IPI
  original_reference_id: PMID:23921388
  review:
    summary: >-
      DNAJB1 binds to the ATPase domain of HSP70 through its J-domain. Jakobsson et al.
      (PMID:23921388) provide context for this interaction in the study of METTL21A
      methylation effects on HSP70 function. ATPase binding is consistent with DNAJB1's
      mechanism of action.
    action: ACCEPT
    reason: >-
      ATPase binding accurately describes DNAJB1's interaction with the ATPase domain
      of HSP70 via its J-domain. This is central to DNAJB1's mechanism of stimulating
      HSP70 ATPase activity.
# ===== Additional Reactome and localization annotations =====
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5690250
  review:
    summary: >-
      Reactome R-HSA-5690250 describes phosphorylation of DNAJB1 by MAPKAPK5 in the cytosol.
      Cytosolic localization of DNAJB1 is well-established and this Reactome annotation is
      consistent.
    action: ACCEPT
    reason: >-
      Cytosol is the primary localization of DNAJB1. The Reactome pathway for MAPKAPK5
      phosphorylation of DNAJB1 correctly places this event in the cytosol.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23921388
  review:
    summary: >-
      PMID:23921388 studies METTL21A methyltransferase and its effects on HSP70. The
      protein binding annotation is uninformative when more specific terms (Hsp70 protein
      binding, ATPase binding) are already present.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. The specific interactions described are already
      captured by Hsp70 protein binding and ATPase binding annotations from the same
      publication.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      Hageman et al. (PMID:21231916) noted that most HSP70/HSPA and HSP40/DNAJ proteins
      are localized in the cytosol. This directly supports cytosolic localization of DNAJB1.
    action: ACCEPT
    reason: >-
      Cytosolic localization is directly stated in PMID:21231916. This is consistent with
      other evidence for DNAJB1 as a primarily cytosolic co-chaperone.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding
        genes and most of the corresponding proteins are localized in the cytosol.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962). This
      IDA annotation from Hageman et al. (PMID:21231916) demonstrated that DNAJB1 interacts
      with unfolded/denatured substrates in the context of the HSP70 chaperone machinery.
      The study assessed effects of overexpression of HSP70/HSPA and HSP40/DNAJ family
      members on refolding of heat-denatured luciferase and suppression of polyQ aggregation.
      DNAJB1 promoted efficient luciferase refolding when paired with HSP70, classifying it
      as a foldase-type co-chaperone. Unlike DNAJB6 and DNAJB8, which have independent
      holdase/anti-aggregation activity, DNAJB1 primarily functions by delivering substrates
      to HSP70 and stimulating HSP70 ATPase activity for the protein folding cycle. UniProt
      confirms that DNAJB1 stimulates ATP hydrolysis and the folding of unfolded proteins
      mediated by HSPA1A/B in vitro (PMID:24318877). The appropriate replacement is
      GO:0044183 (protein folding chaperone), which accurately captures DNAJB1's role in
      binding proteins to assist folding as part of the HSP70 machine.
    action: MODIFY
    reason: >-
      GO:0051082 is scheduled for obsoletion (go-ontology#30962), with the recommended
      replacement being GO:0044183 (protein folding chaperone) for foldase-type chaperones
      or holdase chaperone activity for holdases. Hageman et al. (PMID:21231916) is the
      key reference for this IDA annotation. The paper showed that DNAJB1 belongs to the
      foldase class of J-domain co-chaperones: it promotes luciferase refolding when
      combined with HSP70 but is a poor suppressor of polyQ aggregation. This functional
      classification is consistent with DNAJB1's known mechanism as a class II J-domain
      protein that stimulates HSP70 ATPase activity and delivers substrates to the HSP70
      folding machinery. Additionally, DNAJB1 is a component of the Hsp70 disaggregation
      machinery, working with Hsp70 and HSPA4 to disassemble protein aggregates in an
      ATP-dependent process. The correct replacement term is GO:0044183 (protein folding
      chaperone), defined as binding to a protein or protein-containing complex to assist
      the protein folding process.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:24318877
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        Overexpressed chaperones that suppressed polyQ aggregation were found not to be
        able to stimulate luciferase refolding. Inversely, chaperones that supported
        luciferase refolding were poor suppressors of polyQ aggregation.
    - reference_id: PMID:21231916
      supporting_text: >-
        Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding
        genes and most of the corresponding proteins are localized in the cytosol. To
        test for possible functional differences and/or substrate specificity, we
        assessed the effect of overexpression of each of these HSPs on refolding of
        heat-denatured luciferase and on the suppression of aggregation of a
        non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment.
- term:
    id: GO:0090084
    label: negative regulation of inclusion body assembly
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      Hageman et al. (PMID:21231916) showed that DNAJB1 overexpression suppresses polyQ
      aggregation (inclusion body assembly), though it was a poor suppressor compared to
      holdase-type chaperones like DNAJB6 and DNAJB8. The paper states that chaperones
      that supported luciferase refolding were poor suppressors of polyQ aggregation, and
      DNAJB1 falls into the foldase category.
    action: KEEP_AS_NON_CORE
    reason: >-
      DNAJB1 can negatively regulate inclusion body assembly but is not primarily an
      anti-aggregation chaperone. Hageman et al. (PMID:21231916) showed that foldase-type
      chaperones like DNAJB1 are poor suppressors of polyQ aggregation compared to holdases
      like DNAJB6/DNAJB8. The annotation is valid but represents a minor aspect of DNAJB1
      function. Keep as non-core.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        Overexpressed chaperones that suppressed polyQ aggregation were found not to be
        able to stimulate luciferase refolding. Inversely, chaperones that supported
        luciferase refolding were poor suppressors of polyQ aggregation.
# ===== HDA annotations =====
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  review:
    summary: >-
      PMID:21630459 is a proteomic characterization of the human sperm nucleus. DNAJB1 was
      identified in the sperm nuclear proteome by mass spectrometry. This is consistent with
      known nuclear localization of DNAJB1.
    action: ACCEPT
    reason: >-
      Nuclear localization of DNAJB1 is well-established from UniProt (stress-induced
      translocation) and HPA immunofluorescence. Detection in the sperm nucleus proteome
      by mass spectrometry provides additional supporting evidence.
# ===== Reactome TAS nucleoplasm annotations =====
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371467
  review:
    summary: >-
      Reactome R-HSA-3371467 models SIRT1 deacetylation of HSF1. DNAJB1 is included in
      this pathway as part of the HSF1 regulatory complex in the nucleoplasm.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is consistent with DNAJB1's role in HSF1 regulation in the
      nucleus during heat shock attenuation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371518
  review:
    summary: >-
      Reactome R-HSA-3371518 models SIRT1 binding to HSF1. DNAJB1 participates in the
      nucleoplasmic HSF1 regulatory complex.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization during heat shock response regulation is consistent with
      DNAJB1's known stress-induced nuclear translocation and HSF1 binding activity.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371554
  review:
    summary: >-
      Reactome R-HSA-3371554 models HSF1 acetylation at Lys80. DNAJB1 participates in
      this HSF1 regulatory pathway in the nucleoplasm.
    action: ACCEPT
    reason: >-
      DNAJB1 is part of the HSF1 regulatory complex in the nucleoplasm during heat shock
      attenuation. Consistent with known biology.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5082356
  review:
    summary: >-
      Reactome R-HSA-5082356 models HSF1-mediated gene expression. DNAJB1 is placed in
      the nucleoplasm as part of the HSF1 attenuation mechanism.
    action: ACCEPT
    reason: >-
      DNAJB1 localizes to the nucleoplasm during the heat shock response to participate
      in HSF1 regulation. Consistent with UniProt and PMID:9499401.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5082369
  review:
    summary: >-
      Reactome R-HSA-5082369 models acetylated HSF1 dissociation from DNA. DNAJB1 is
      part of the HSF1 attenuation complex in the nucleoplasm.
    action: ACCEPT
    reason: >-
      DNAJB1 nucleoplasm localization is consistent with its role in HSF1 regulation
      during heat shock attenuation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5082384
  review:
    summary: >-
      Reactome R-HSA-5082384 specifically models HSP70:DNAJB1 binding HSF1 in the
      nucleoplasm. Shi et al. (PMID:9499401) showed that Hsp70 and Hdj1 interact with
      the HSF1 activation domain and repress transcription.
    action: ACCEPT
    reason: >-
      This Reactome entry directly models the DNAJB1-HSP70-HSF1 interaction in the
      nucleoplasm, which is a well-characterized mechanism of heat shock attenuation
      (PMID:9499401).
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5251955
  review:
    summary: >-
      Reactome R-HSA-5251955 models HSP40s activating HSP70 ATPase activity in the
      nucleoplasm. DNAJB1 is explicitly listed as one of the HSP40s that stimulates
      HSP70 ATPase activity in this compartment.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is consistent with DNAJB1's nuclear translocation under
      heat shock and its ATPase activator function in the nucleoplasm.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  review:
    summary: >-
      PMID:19056867 is a large-scale proteomics study of urinary exosomes. Detection of
      DNAJB1 in exosomes by mass spectrometry may represent passive inclusion rather than
      specific exosomal targeting.
    action: KEEP_AS_NON_CORE
    reason: >-
      Detection in extracellular exosomes by proteomics (PMID:19056867) is valid but
      represents a non-specific finding. Many cytosolic proteins are found in exosomes
      without specific functional significance. Keep as non-core.
# ===== Additional Reactome cytosol annotations =====
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5251959
  review:
    summary: >-
      Reactome R-HSA-5251959 models HSP40s activating HSP70 ATPase activity in the cytosol.
      DNAJB1 is one of the HSP40s that activates HSP70 ATPase in the cytosol.
    action: ACCEPT
    reason: >-
      Cytosol is the primary location of DNAJB1. The Reactome pathway correctly places
      DNAJB1 ATPase activator function in the cytosol.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5690245
  review:
    summary: >-
      Reactome R-HSA-5690245 models the binding of phosphorylated MAPKAPK5 to DNAJB1 in
      the cytosol. Cytosolic localization is consistent with known DNAJB1 biology.
    action: ACCEPT
    reason: >-
      Cytosol localization is consistent with DNAJB1 primary localization. The Reactome
      pathway for MAPKAPK5 binding to DNAJB1 correctly places this interaction in the
      cytosol.
# ===== IDA protein folding from PMID:18620420 =====
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:18620420
  review:
    summary: >-
      Moffatt et al. (PMID:18620420) studied the role of the cochaperone Tpr2 in Hsp90
      chaperoning. The paper mentions that Tpr2 replaced type I and II J proteins (including
      DNAJB1-type) in Hsp90-dependent chaperoning. DNAJB1 participation in protein folding
      through the Hsp90 chaperone cycle is consistent with its co-chaperone function.
    action: ACCEPT
    reason: >-
      Protein folding is a core function of DNAJB1. PMID:18620420 provides evidence that
      J proteins including type II (DNAJB1 class) participate in Hsp90-dependent protein
      folding. While the paper focuses on Tpr2, it demonstrates DNAJB1-class J protein
      involvement in the chaperone folding cycle.
    supported_by:
    - reference_id: PMID:18620420
      supporting_text: >-
        Tpr2 replaced type I and II J proteins in the Hsp90-dependent chaperoning of the
        PR and the protein kinase, Chk1.
# ===== TAS response to unfolded protein =====
- term:
    id: GO:0006986
    label: response to unfolded protein
  evidence_type: TAS
  original_reference_id: PMID:8975727
  review:
    summary: >-
      Hata et al. (PMID:8975727) cloned the genomic DNA for human Hsp40 (DNAJB1) and
      characterized its gene structure. The 5-prime region contains typical heat shock
      elements, indicating stress-responsive expression consistent with response to
      unfolded protein.
    action: ACCEPT
    reason: >-
      DNAJB1 (Hsp40) is a heat shock protein with heat shock elements in its promoter
      (PMID:8975727), indicating stress-responsive induction. As a co-chaperone for HSP70
      that assists in folding unfolded proteins, response to unfolded protein is an
      appropriate biological process annotation.
    supported_by:
    - reference_id: PMID:8975727
      supporting_text: >-
        The 5' region of the gene is highly GC rich, and there are multiple basal elements
        for transcription factors including typical heat shock elements.
core_functions:
  - molecular_function:
      id: GO:0044183
      label: protein folding chaperone
    description: >-
      DNAJB1 is a class B J-domain co-chaperone (foldase-type) that binds unfolded/misfolded
      protein substrates via its C-terminal beta-sandwich domains (CTD-I and CTD-II) and
      delivers them to HSP70 for productive ATP-dependent refolding. DNAJB1 stimulates the
      ATPase activity of HSP70 via its J-domain HPD motif and promotes substrate release
      and refolding. A distinctive feature of DNAJB1 is G/F-mediated autoinhibition of
      its J-domain, which is relieved by a secondary contact between Hsp70's EEVD motif
      and a positively charged groove in CTD-I, enabling productive Hsp70 engagement
      (DOI:10.1016/j.tcb.2022.05.004). DNAJB1 also participates in disaggregation by
      remaining associated with protein aggregates and scaffolding multiple Hsp70 molecules
      through JDP hetero-oligomerization. Classified as a foldase rather than holdase based
      on its ability to support luciferase refolding and poor suppression of polyQ
      aggregation (PMID:21231916).
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          chaperones that supported luciferase refolding were poor suppressors of polyQ
          aggregation.
      - reference_id: PMID:24318877
        supporting_text: >-
          we combined the Hsp70-NEF pairs with cochaperones of the J protein family (DnaJA1,
          DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The activity of the
          combinations in ATPase and luciferase refolding assays were dependent on the
          identity and stoichiometry of both the J protein and NEF
    directly_involved_in:
      - id: GO:0006457
        label: protein folding
      - id: GO:1903334
        label: positive regulation of protein folding
      - id: GO:0006986
        label: response to unfolded protein
      - id: GO:0034605
        label: cellular response to heat
      - id: GO:1900034
        label: regulation of cellular response to heat
    locations:
      - id: GO:0005829
        label: cytosol
      - id: GO:0005654
        label: nucleoplasm
      - id: GO:0005730
        label: nucleolus
  - molecular_function:
      id: GO:0001671
      label: ATPase activator activity
    description: >-
      DNAJB1 stimulates the intrinsic ATPase activity of HSP70 family members (HSPA1A/B)
      through its J-domain HPD motif, which docks on ATP-bound Hsp70 at the interdomain
      linker and positions the HPD motif to activate Hsp70's catalytic center
      (DOI:10.1016/j.tcb.2022.05.004). This stimulation shifts Hsp70 to a high-affinity
      client-binding state ("ultra-affinity"), driving the HSP70 chaperone cycle for
      substrate binding, folding, and release. Nucleotide exchange factors then promote
      ADP release to reset the cycle. Directly demonstrated in vitro using purified
      components with varying Hsp70-NEF combinations (PMID:24318877). The J-domain
      activity is subject to G/F-mediated autoinhibition in class B JDPs, requiring
      Hsp70 EEVD-mediated relief for full activation.
    supported_by:
      - reference_id: PMID:24318877
        supporting_text: >-
          we combined the Hsp70-NEF pairs with cochaperones of the J protein family (DnaJA1,
          DnaJA2, DnaJB1, and DnaJB4) to generate 16 permutations. The activity of the
          combinations in ATPase and luciferase refolding assays were dependent on the
          identity and stoichiometry of both the J protein and NEF
      - reference_id: PMID:23921388
        supporting_text: >-
          Hsp70 proteins constitute an evolutionarily conserved protein family of
          ATP-dependent molecular chaperones involved in a wide range of biological
          processes.
    directly_involved_in:
      - id: GO:0006457
        label: protein folding
    locations:
      - id: GO:0005829
        label: cytosol
      - id: GO:0005654
        label: nucleoplasm
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:17024176
  title: A novel HSF1-mediated death pathway that is suppressed by heat shock proteins.
  findings: []
- id: PMID:18620420
  title: Role of the cochaperone Tpr2 in Hsp90 chaperoning.
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:20060297
  title: Chaperone-assisted selective autophagy is essential for muscle maintenance.
  findings: []
- id: PMID:21044950
  title: Genome-wide YFP fluorescence complementation screen identifies new regulators
    for telomere signaling in human cells.
  findings: []
- id: PMID:21163940
  title: Interactome mapping suggests new mechanistic details underlying Alzheimer's
    disease.
  findings: []
- id: PMID:21231916
  title: The diverse members of the mammalian HSP70 machine show distinct chaperone-like
    activities.
  findings: []
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
- id: PMID:23921388
  title: Identification and characterization of a novel human methyltransferase modulating
    Hsp70 protein function through lysine methylation.
  findings: []
- id: PMID:24318877
  title: Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70)
    generates functionally distinct complexes in vitro.
  findings: []
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of
    cellular protein homeostasis pathways.
  findings: []
- id: PMID:25468996
  title: E-cadherin interactome complexity and robustness resolved by quantitative
    proteomics.
  findings: []
- id: PMID:27120771
  title: Polyhydramnios, Transient Antenatal Bartter's Syndrome, and MAGED2 Mutations.
  findings: []
- id: PMID:27173435
  title: An organelle-specific protein landscape identifies novel diseases and molecular
    mechanisms.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:36931259
  title: A central chaperone-like role for 14-3-3 proteins in human cells.
  findings: []
- id: PMID:8975727
  title: Genomic cloning of a human heat shock protein 40 (Hsp40) gene (HSPF1) and
    its chromosomal localization to 19p13.2.
  findings: []
- id: PMID:9499401
  title: Molecular chaperones as HSF1-specific transcriptional repressors.
  findings: []
- id: Reactome:R-HSA-3371453
  title: Regulation of HSF1-mediated heat shock response
  findings: []
- id: Reactome:R-HSA-3371467
  title: SIRT1 deacetylates HSF1
  findings: []
- id: Reactome:R-HSA-3371518
  title: SIRT1 binds to HSF1
  findings: []
- id: Reactome:R-HSA-3371554
  title: HSF1 acetylation at Lys80
  findings: []
- id: Reactome:R-HSA-5082356
  title: HSF1-mediated gene expression
  findings: []
- id: Reactome:R-HSA-5082369
  title: Acetylated HSF1 dissociates from DNA
  findings: []
- id: Reactome:R-HSA-5082384
  title: HSP70:DNAJB1 binds HSF1
  findings: []
- id: Reactome:R-HSA-5251955
  title: HSP40s activate intrinsic ATPase activity of HSP70s in the nucleoplasm
  findings: []
- id: Reactome:R-HSA-5251959
  title: HSP40s activate intrinsic ATPase activity of HSP70s in the cytosol
  findings: []
- id: Reactome:R-HSA-5690245
  title: p-T182 MAPKAPK5 binds DNAJB1
  findings: []
- id: Reactome:R-HSA-5690250
  title: p-T182-MAPKAPK5 phoshphorylates DNAJB1
  findings: []
- id: DOI:10.1016/j.tcb.2022.05.004
  title: J-domain protein chaperone circuits in proteostasis and disease.
  findings:
    - statement: >-
        Class B JDPs (including DNAJB1) have G/F-mediated autoinhibition of the
        J-domain; interaction between Hsp70's EEVD motif and DNAJB1 CTD-I relieves
        this autoinhibition for productive Hsp70 engagement.
    - statement: >-
        JDP scaffolding and hetero-oligomerization, including DNAJB1 participation,
        creates potent Hsp70-based disaggregases; DNAJB1 remains associated with
        aggregates to recruit multiple Hsp70 molecules.
- id: DOI:10.3390/ijms222413527
  title: Regulation of p53 and cancer signaling by heat shock protein 40/J-domain
    protein family members.
  findings:
    - statement: >-
        DNAJB1/HDJ1 binds and stabilizes MDM2 and destabilizes PDCD5, modulating
        p53-mediated apoptosis; can also support mutant p53 gain-of-function
        phenotypes in context-dependent manner.

DNAJB1

Gene Description

Existing Annotations Review

Core Functions

References

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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