DNAJB2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0001671 ATPase activator activity	IBA GO_REF:0000033	ACCEPT	Summary: DNAJB2 (HSJ1) stimulates the ATPase activity of HSP70/Hsc70 via its conserved J domain. Cheetham et al. (1994) showed that both HSJ1a and HSJ1b enhance the weak intrinsic ATPase activity of constitutive Hsc70 more than fivefold (PMID:7957263). Gao et al. (2012) confirmed that the J domain of HSJ1a mediates interaction with and ATPase activation of HSP70 (PMID:22219199). The IBA annotation is phylogenetically sound for J-domain proteins, and the term accurately captures a core molecular function of DNAJB2. Reason: ATPase activator activity is a well-established core function of DNAJB2 as a J-domain co-chaperone. Multiple experimental studies confirm this function (PMID:7957263, PMID:22219199). The IBA annotation is consistent with the conserved role of the J domain across the DnaJ family. Supporting Evidence: PMID:7957263 The weak intrinsic ATPase activity of the constitutive 70-kDa heat-shock protein is enhanced more than fivefold by stoichiometric amounts of both HSJ1a and HSJ1b. PMID:22219199 The J domain of HSJ1a shares a conserved structure with other J domains from both eukaryotic and prokaryotic species, and it mediates the interaction with and the ATPase cycle of HSP70. file:human/DNAJB2/DNAJB2-deep-research-falcon.md DNAJB2 "traffics unfolded proteins" to Hsp70 and stimulates Hsp70 ATPase activity via its J-domain, a canonical JDP activity.
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: DNAJB2 isoform 2 (HSJ1a) is cytoplasmic/cytosolic (PMID:12754272). UniProt confirms that isoform 2 localizes to cytoplasm. Hageman et al. (2011) showed cytosolic localization by immunofluorescence (PMID:21231916). The IBA annotation to cytosol is appropriate as HSJ1a is the primary cytosolic isoform. Note that isoform 1 (HSJ1b) is ER-membrane anchored. Reason: Cytosol is a well-supported localization for DNAJB2 isoform HSJ1a. Multiple experimental studies (PMID:12754272, PMID:21231916) confirm cytoplasmic/cytosolic localization. The IBA annotation is phylogenetically reasonable for J-domain proteins. 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:0030544 Hsp70 protein binding	IBA GO_REF:0000033	ACCEPT	Summary: DNAJB2 physically interacts with HSP70 family members through its J domain. Cheetham et al. (1994) demonstrated in vitro interaction between HSJ1a/HSJ1b and constitutive Hsc70 (PMID:7957263). Gao et al. (2012) confirmed the J domain of HSJ1a binds HSP70 and determined the structural basis for this interaction (PMID:22219199). UniProt records interactions with HSPA1A, HSPA1B, and HSPA8 (Hsc70). The IBA annotation is well-supported for all J-domain proteins and represents a core function of DNAJB2. Reason: Hsp70 protein binding is a fundamental and experimentally validated function of DNAJB2. Multiple studies confirm the J-domain-mediated physical interaction with HSP70/Hsc70 (PMID:7957263, PMID:22219199, PMID:21625540). This is a core molecular function. Supporting Evidence: PMID:22219199 The J-domain co-chaperones work together with the heat shock protein 70 (HSP70) chaperone to regulate many cellular events, but the mechanism underlying the J-domain-mediated HSP70 function remains elusive. PMID:7957263 The weak intrinsic ATPase activity of the constitutive 70-kDa heat-shock protein is enhanced more than fivefold by stoichiometric amounts of both HSJ1a and HSJ1b.
GO:0042026 protein refolding	IBA GO_REF:0000033	ACCEPT	Summary: DNAJB2 participates in protein refolding as part of the HSP70 chaperone machine. Hageman et al. (2011) systematically assessed HSP40/DNAJ family members for refolding of heat-denatured luciferase and suppression of polyQ aggregation (PMID:21231916). DNAJB2 showed chaperone-like activities in these assays. The IBA annotation to protein refolding is phylogenetically reasonable for J-domain proteins that assist HSP70 in protein refolding. Reason: Protein refolding is a well-characterized function of DNAJB2 as an HSP70 co-chaperone. Experimental data from Hageman et al. (2011) support this annotation (PMID:21231916), and the IBA phylogenetic inference is sound for J-domain co-chaperones. 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:0051082 unfolded protein binding	IBA GO_REF:0000033	MODIFY	Summary: GO:0051082 (unfolded protein binding) is now formally obsolete (go-ontology#30962). DNAJB2 is a J-domain containing HSP40 co-chaperone that functions by binding to misfolded/unfolded proteins in the context of the HSP70 chaperone machine, not as an independent unfolded protein binder. The IBA annotation via PANTHER is phylogenetically reasonable for J-domain proteins in general, but the term itself is being replaced. The correct replacement is GO:0044183 (protein folding chaperone), which accurately captures DNAJB2's role in assisting protein folding as an HSP70 co-chaperone. UniProt describes it as functioning as a co-chaperone that regulates substrate binding and activates ATPase activity of HSP70 family chaperones (PMID:22219199, PMID:7957263). Hageman et al. (2011) showed DNAJB2 has chaperone-like activities including protein refolding and suppression of aggregation (PMID:21231916). Reason: GO:0051082 is now formally obsolete. DNAJB2 functions as a protein folding chaperone (HSP70 co-chaperone) via its J domain, not as a standalone unfolded protein binder. GO:0044183 (protein folding chaperone) is the appropriate replacement term, as it captures the functional role of binding to proteins to assist the folding process. Proposed replacements: protein folding 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. 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:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: This IEA annotation derives from UniProtKB subcellular location vocabulary mapping. UniProt records that isoform 2 (HSJ1a) localizes to the nucleus (PMID:12754272). Chapple and Cheetham (2003) showed nuclear localization for HSJ1a, and Hageman et al. (2011) confirmed nucleus localization by IDA (PMID:21231916). The IEA mapping is consistent with experimental data. HSJ1a is found in both cytoplasm and nucleus. Reason: Nuclear localization of DNAJB2 isoform HSJ1a is experimentally supported by IDA evidence (PMID:21231916, PMID:12754272). The IEA annotation correctly reflects the UniProt subcellular location entry. This is a broader IEA that is acceptable alongside the more specific IDA evidence.
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: This IEA annotation from combined automated methods maps DNAJB2 to cytoplasm. UniProt records isoform 2 (HSJ1a) in the cytoplasm (PMID:12754272, PMID:21625540). This is a broader localization term compared to cytosol (GO:0005829), and is correct for HSJ1a. The IEA annotation is consistent with experimental data. Reason: Cytoplasm localization is experimentally confirmed for DNAJB2 isoform HSJ1a (PMID:12754272, PMID:21625540). Although cytosol (GO:0005829) is more specific and also annotated, this broader IEA annotation is acceptable.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: This IEA annotation maps from UniProt subcellular location vocabulary. UniProt records that isoform 1 (HSJ1b) localizes to the endoplasmic reticulum membrane via C-terminal geranylgeranylation at Cys-321, on the cytoplasmic side (PMID:12754272). Chapple and Cheetham (2003) showed that HSJ1b is anchored to the ER membrane and that mutation of C321S causes relocalization. This annotation is isoform-specific to HSJ1b but is appropriately captured for the gene product. Reason: ER membrane localization is experimentally confirmed for DNAJB2 isoform HSJ1b via geranylgeranylation (PMID:12754272). The IEA annotation correctly reflects the UniProt subcellular location. While isoform-specific, this is a valid annotation for the gene product.
GO:0030544 Hsp70 protein binding	IEA GO_REF:0000002	ACCEPT	Summary: This IEA annotation derives from InterPro domain mapping (IPR043183, DNJB2/6-like domain). HSP70 protein binding is a core function of DNAJB2 mediated by the J domain. This is well supported by multiple experimental studies (PMID:7957263, PMID:22219199, PMID:21625540). The InterPro mapping is correct. Reason: The InterPro-derived IEA annotation to Hsp70 protein binding is accurate for DNAJB2 as a J-domain protein. This is experimentally validated (PMID:7957263, PMID:22219199) and represents a core molecular function.
GO:0051082 unfolded protein binding	IEA GO_REF:0000002	MODIFY	Summary: GO:0051082 (unfolded protein binding) is now formally obsolete (go-ontology#30962). This IEA annotation is based on InterPro mapping (IPR043183, the DNJB2/6-like domain). DNAJB2 is classified as a J-domain protein / HSP40 co-chaperone whose function is to assist HSP70 in protein folding, not to independently bind unfolded proteins. The InterPro-derived mapping should be updated to reflect the replacement term GO:0044183 (protein folding chaperone), which accurately describes the chaperone function of J-domain proteins. Reason: GO:0051082 is now formally obsolete. The IEA annotation from InterPro (IPR043183) correctly identifies DNAJB2 as having a DNJB2/6-like domain associated with chaperone function, but the target term should be updated to GO:0044183 (protein folding chaperone), which better captures the co-chaperone role of J-domain proteins in assisting protein folding. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:24023695 The molecular chaperone HSJ1 (DNAJB2) is a member of the Hsp40 (or DnaJ) family of heat shock proteins that contain a J domain, which is crucial in substrate recognition by Hsp70 [21], [22], [23]. Thus, Hsp40/DnaJ protein function is essential for Hsp70 function, including protein folding and directing misfolded proteins towards the proteasome [23].
GO:0051087 protein-folding chaperone binding	IEA GO_REF:0000117	ACCEPT	Summary: This IEA annotation from ARBA machine learning (GO_REF:0000117) maps DNAJB2 to protein-folding chaperone binding. DNAJB2 binds HSP70 family chaperones (HSPA1A, HSPA1B, HSPA8) via its J domain (PMID:7957263, PMID:22219199, PMID:21625540). HSP70 proteins are protein-folding chaperones, so this annotation is accurate. There is also IPI evidence for this same term (PMID:21231916). Reason: The IEA annotation is consistent with DNAJB2's well-characterized binding to HSP70 chaperones. Experimentally confirmed by multiple studies and also annotated with IPI evidence.
GO:0090084 negative regulation of inclusion body assembly	IEA GO_REF:0000117	ACCEPT	Summary: This IEA annotation from ARBA machine learning captures DNAJB2's role in suppressing protein aggregation and inclusion body formation. Multiple studies show that HSJ1a suppresses inclusion formation by polyglutamine-expanded proteins (PMID:21231916) and mutant SOD1 (PMID:24023695). There is also IDA evidence for the same term (PMID:21231916). The automated annotation is consistent with experimentally demonstrated function. Reason: Negative regulation of inclusion body assembly is well supported by experimental evidence (PMID:21231916, PMID:24023695). DNAJB2 reduces inclusion formation through its J domain and UIM domain activities. The IEA annotation is consistent with IDA evidence.
GO:0005515 protein binding	IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc...	REMOVE	Summary: This IPI annotation from Taipale et al. (2014) derives from a large-scale chaperone interaction network study. The with/from column indicates interaction with MLF1 (P58340). While the interaction may be real, GO:0005515 (protein binding) is uninformative and does not specify the nature of the interaction. DNAJB2 has more specific binding annotations (Hsp70 protein binding, ubiquitin binding, protein-folding chaperone binding) that are more informative. Reason: Protein binding (GO:0005515) is uninformative for DNAJB2. More specific molecular function binding terms are already annotated (GO:0030544 Hsp70 protein binding, GO:0043130 ubiquitin binding, GO:0051087 protein-folding chaperone binding). Per curation guidelines, this vague term should be replaced by more informative annotations.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: This IPI annotation from Huttlin et al. (2021) BioPlex proteome-scale interactome study (with/from MLF1, P58340). As with the other protein binding annotation, GO:0005515 is uninformative. More specific binding terms already capture DNAJB2's binding functions. Reason: Protein binding (GO:0005515) is uninformative. More specific molecular function binding terms are already annotated for DNAJB2. This vague annotation does not add functional information.
GO:0031965 nuclear membrane	IDA GO_REF:0000052	UNDECIDED	Summary: This IDA annotation from HPA (Human Protein Atlas) immunofluorescence data places DNAJB2 at the nuclear membrane. UniProt records that isoform 2 (HSJ1a) localizes to cytoplasm and nucleus (PMID:12754272). Nuclear membrane localization is plausible but not specifically described in the primary literature for DNAJB2. The HPA immunofluorescence may be detecting perinuclear ER-associated HSJ1b or nuclear-peripheral HSJ1a. This is not a well-characterized localization for DNAJB2 in the literature. Reason: Nuclear membrane localization comes from HPA immunofluorescence data (GO_REF:0000052), not from primary DNAJB2 literature. While DNAJB2 is found in nucleus and ER membrane, nuclear membrane specifically is not discussed in the primary literature. Without access to the HPA images or detailed characterization, this cannot be fully evaluated.
GO:0120283 protein serine/threonine kinase binding	IPI PMID:28031292 Protein kinase CK2 modulates HSJ1 function through phosphory...	ACCEPT	Summary: Ottaviani et al. (2017) showed that CK2 (protein kinase CK2, comprising CSNK2A1/P68400 and CSNK2A2/P19784 catalytic subunits) phosphorylates DNAJB2 at Ser250 and Ser247 within its UIM2 domain (PMID:28031292). The GOA with/from column lists P19784 (CSNK2A2) and P68400 (CSNK2A1). CK2 is a serine/threonine kinase, so the annotation to protein serine/threonine kinase binding accurately captures the demonstrated physical interaction. Reason: DNAJB2 is a confirmed substrate of CK2. Ottaviani et al. (2017) demonstrated direct phosphorylation and physical interaction between CK2 and HSJ1 in vitro and in cells (PMID:28031292). The term accurately describes the interaction. Supporting Evidence: PMID:28031292 Here we show that CK2, a ubiquitous and constitutively active protein kinase, phosphorylates HSJ1 within its second UIM, at the dominant site Ser250 and the hierarchical site Ser247.
GO:0140318 protein transporter activity	TAS PMID:28031292 Protein kinase CK2 modulates HSJ1 function through phosphory...	ACCEPT	Summary: This TAS annotation from ARUK-UCL references PMID:28031292 (Ottaviani et al. 2017). The paper describes DNAJB2 as a "shuttling factor to sort chaperone clients to the proteasome" (citing Westhoff et al. 2005, PMID:15936278). DNAJB2 facilitates delivery of ubiquitylated misfolded proteins to the proteasome. GO:0140318 covers direct binding to a protein cargo and delivery of that cargo to a cellular destination, so it is appropriate for DNAJB2's shuttling-factor role in delivering ubiquitylated clients to the proteasome. Reason: DNAJB2/HSJ1 binds ubiquitylated client proteins through its UIMs and facilitates their delivery to the proteasome. This satisfies protein transporter activity in the protein- cargo delivery sense and does not require transmembrane transport. Supporting Evidence: PMID:28031292 HSJ1 (also known as DNAJB2) is a key component in neuronal protein quality control. It is a molecular chaperone that is preferentially expressed in neurons that can act as a shuttling factor to sort chaperone clients to the proteasome (1).
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process	TAS PMID:28031292 Protein kinase CK2 modulates HSJ1 function through phosphory...	ACCEPT	Summary: This TAS annotation captures DNAJB2's role in promoting proteasomal degradation of ubiquitylated client proteins. Ottaviani et al. (2017) describe HSJ1 as binding ubiquitylated proteins through its UIMs and facilitating their delivery to the proteasome (PMID:28031292). Westhoff et al. (2005) showed HSJ1 acts as a shuttling factor for sorting chaperone clients to the proteasome (PMID:15936278). Gao et al. (2011) demonstrated HSJ1a promotes HSP70-mediated proteasomal degradation of ataxin-3 (PMID:21625540). This is a core function of DNAJB2. Reason: Positive regulation of proteasomal ubiquitin-dependent protein catabolism is a well-characterized core function of DNAJB2, mediated through its UIM domains that bind ubiquitylated substrates and its J domain that engages HSP70. Multiple studies confirm this (PMID:28031292, PMID:15936278, PMID:21625540, PMID:24023695). Supporting Evidence: PMID:28031292 It binds ubiquitylated proteins through its Ubiquitin Interacting Motifs (UIMs) and facilitates their delivery to the proteasome for degradation. PMID:21625540 The J-domain down-regulates the protein level of Atx3 through HSP70 mediated proteasomal degradation, while the UIM domain may alleviate this process via maintaining the ubiquitinated Atx3.
GO:0043130 ubiquitin binding	IDA PMID:28031292 Protein kinase CK2 modulates HSJ1 function through phosphory...	ACCEPT	Summary: DNAJB2 contains two ubiquitin-interacting motifs (UIMs) that bind ubiquitin chains. Ottaviani et al. (2017) directly demonstrated ubiquitin binding through co-immunoprecipitation of HSJ1a-associated ubiquitylated proteins, and showed that CK2 phosphorylation of the UIM2 domain reduces this binding (PMID:28031292). Gao et al. (2011) showed UIM domains bind K48- and K63-linked diubiquitin chains, with UIM2 being more important (PMID:21625540). Westhoff et al. (2005) showed UIM mutation abolishes polyubiquitin chain binding (PMID:15936278). However, the more specific term GO:0031593 (polyubiquitin modification-dependent protein binding) or GO:0140036 (ubiquitin-modified protein reader activity) may be more appropriate, as DNAJB2 specifically reads ubiquitin modifications on client proteins. Reason: Ubiquitin binding via UIM domains is a core function of DNAJB2 directly demonstrated by IDA evidence (PMID:28031292). While more specific terms exist, this annotation is accurate and supported by multiple studies. Supporting Evidence: PMID:28031292 Near the C-terminus HSJ1 has two Ubiquitin Interacting Motifs (UIMs), that function to bind ubiquitin chains and help prevent client protein aggregation.
GO:0070050 neuron cellular homeostasis	TAS PMID:28031292 Protein kinase CK2 modulates HSJ1 function through phosphory...	KEEP AS NON CORE	Summary: This TAS annotation from ARUK-UCL references PMID:28031292. Ottaviani et al. (2017) describe HSJ1 as "a key component in neuronal protein quality control" and note that DNAJB2 mutations cause hereditary neuropathies (PMID:28031292). DNAJB2 is preferentially expressed in neurons and maintains proteostasis there. However, "neuron cellular homeostasis" (GO:0070050) is a very broad biological process term. DNAJB2's role is specifically in protein quality control and proteostasis in neurons, not in all aspects of neuronal homeostasis. Reason: While DNAJB2 is clearly important for neuronal protein homeostasis (mutations cause neuropathy), the term "neuron cellular homeostasis" is broad. DNAJB2's contribution is specifically through protein quality control. This is a downstream consequence of its core chaperone/ubiquitin-binding functions rather than a direct molecular activity. Supporting Evidence: PMID:28031292 HSJ1 (also known as DNAJB2) is a key component in neuronal protein quality control. It is a molecular chaperone that is preferentially expressed in neurons that can act as a shuttling factor to sort chaperone clients to the proteasome (1).
GO:0140036 ubiquitin-modified protein reader activity	IDA PMID:28031292 Protein kinase CK2 modulates HSJ1 function through phosphory...	ACCEPT	Summary: DNAJB2 reads ubiquitin modifications on client proteins via its two UIM domains and sorts them for proteasomal degradation. Ottaviani et al. (2017) showed by co-immunoprecipitation that HSJ1a binds ubiquitylated clients, and this binding is reduced by CK2 phosphorylation of UIM2 or by UIM-disrupting mutations (PMID:28031292). This term captures the specific activity of recognizing ubiquitin modifications to direct protein fate, which is more precise than simple ubiquitin binding. Reason: Ubiquitin-modified protein reader activity precisely describes DNAJB2's UIM-mediated recognition of ubiquitylated substrates for proteasomal targeting. This is experimentally confirmed by IDA evidence (PMID:28031292) and represents a core molecular function that distinguishes DNAJB2 from other J-domain proteins. Supporting Evidence: PMID:28031292 It binds ubiquitylated proteins through its Ubiquitin Interacting Motifs (UIMs) and facilitates their delivery to the proteasome for degradation.
GO:0005515 protein binding	IPI PMID:21625540 Co-chaperone HSJ1a dually regulates the proteasomal degradat...	REMOVE	Summary: This IPI annotation from Gao et al. (2011) records DNAJB2 self-interaction (with/from P25686-2, HSJ1a isoform). The paper shows HSJ1a interaction with HSP70 and ataxin-3, and the with/from suggesting self-interaction may reflect co-immunoprecipitation artifacts. Regardless, GO:0005515 (protein binding) is uninformative. DNAJB2's interactions are better captured by specific binding terms already annotated. Reason: Protein binding (GO:0005515) is uninformative. DNAJB2's specific binding interactions are already captured by GO:0030544 (Hsp70 protein binding), GO:0043130 (ubiquitin binding), GO:0051087 (protein-folding chaperone binding), and GO:0140036 (ubiquitin-modified protein reader activity).
GO:0008285 negative regulation of cell population proliferation	IGI PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor supp...	REMOVE	Summary: This IGI annotation from Maheswaran et al. (1998) derives from a study of the Wilms tumor suppressor WT1, not DNAJB2 specifically. The paper showed that WT1-mediated growth inhibition requires association with Hsp70, and that substitution of a heterologous Hsp70-binding domain derived from "human DNAJ" could restore WT1 function (PMID:9553041). This is a chimeric construct experiment; the J domain of an unspecified human DnaJ protein was fused to WT1 to test whether Hsp70 binding mediates growth suppression. DNAJB2 is not the gene under study, and the observation is about WT1 function, not DNAJB2 function. Reason: PMID:9553041 studies WT1 tumor suppressor function, not DNAJB2. The paper used a generic "human DNAJ" domain as a tool to provide Hsp70-binding capability to WT1. Negative regulation of cell proliferation is not a function of DNAJB2; it is a function of WT1. The IGI annotation incorrectly attributes a WT1 phenotype to DNAJB2. Supporting Evidence: PMID:9553041 Substitution of a heterologous Hsp70-binding domain derived from human DNAJ is sufficient to restore the functional properties of a WT1 protein with an amino-terminal deletion, an effect that is abrogated by a point mutation in DNAJ that reduces binding to Hsp70.
GO:0030308 negative regulation of cell growth	IGI PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor supp...	REMOVE	Summary: Same as the GO:0008285 annotation above - this IGI annotation from Maheswaran et al. (1998) derives from a WT1 study where a human DNAJ J domain was used as a chimeric tool. The growth inhibition is a property of WT1, not DNAJB2. DNAJB2's J domain was used merely to provide Hsp70-binding capability to test WT1 function. Reason: PMID:9553041 is about WT1 function, not DNAJB2. The DNAJ J domain was used as a heterologous tool in a chimeric construct. Negative regulation of cell growth is a WT1 function, not a DNAJB2 function. This annotation incorrectly attributes a WT1 phenotype to DNAJB2. Supporting Evidence: PMID:9553041 Substitution of a heterologous Hsp70-binding domain derived from human DNAJ is sufficient to restore the functional properties of a WT1 protein with an amino-terminal deletion, an effect that is abrogated by a point mutation in DNAJ that reduces binding to Hsp70.
GO:0051087 protein-folding chaperone binding	IPI PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	ACCEPT	Summary: This IPI annotation from Hageman et al. (2011) is based on the demonstrated interaction between DNAJB2 and HSP70 family members (with/from P0DMV8/HSPA1A, P0DMV9/HSPA1B, P17066/HSPA6). The study systematically characterized interactions between HSP40/DNAJ and HSP70/HSPA family members and demonstrated that DNAJB2 interacts with HSP70 proteins that are protein-folding chaperones (PMID:21231916). This is a core molecular function. Reason: Protein-folding chaperone binding is experimentally validated by co-expression studies showing DNAJB2 interaction with HSP70 chaperones HSPA1A, HSPA1B, and HSPA6 (PMID:21231916). This is a core function of DNAJB2 as a J-domain 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. 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:0006457 protein folding	IMP PMID:24023695 Molecular chaperone mediated late-stage neuroprotection in t...	ACCEPT	Summary: This IMP annotation from Novoselov et al. (2013) is based on data showing that HSJ1a overexpression reduces SOD1(G93A) aggregation and improves motor neuron survival in vivo (PMID:24023695). The J domain mutant H31Q lost the ability to suppress aggregation while the UIM mutant was partially functional. The paper describes HSJ1a as acting through "chaperone, co-chaperone and pro-ubiquitylation activity." Protein folding is an appropriate biological process for DNAJB2's role in maintaining protein homeostasis. Reason: Protein folding is a core biological process for DNAJB2 as an HSP70 co-chaperone. The IMP evidence from mutant phenotype studies (J domain and UIM mutants affecting SOD1 aggregation) supports DNAJB2's role in protein folding/quality control (PMID:24023695). Supporting Evidence: PMID:24023695 HSJ1a preferentially bound to mutant SOD1, enhanced SOD1 ubiquitylation and reduced SOD1 aggregation in a J-domain and ubiquitin interaction motif (UIM) dependent manner. Collectively, the data suggest that HSJ1a acts on mutant SOD1 through a combination of chaperone, co-chaperone and pro-ubiquitylation activity.
GO:0031396 regulation of protein ubiquitination	IMP PMID:24023695 Molecular chaperone mediated late-stage neuroprotection in t...	ACCEPT	Summary: This IMP annotation from Novoselov et al. (2013) is based on data showing that HSJ1a enhances SOD1 ubiquitylation in a UIM-dependent manner (PMID:24023695). The UIM mutant did not enhance SOD1 ubiquitylation, while wild-type HSJ1a strongly increased ubiquitin immunoreactivity on SOD1 upon proteasome inhibition. Gao et al. (2011) also showed HSJ1a regulates ubiquitination of ataxin-3 (PMID:21625540). This is a core function linked to DNAJB2's UIM domains. Reason: Regulation of protein ubiquitination is a well-characterized function of DNAJB2 mediated by its UIM domains. IMP evidence from mutant studies confirms this (PMID:24023695, PMID:21625540). This is a core biological process for DNAJB2. Supporting Evidence: PMID:24023695 HSJ1a preferentially bound to mutant SOD1, enhanced SOD1 ubiquitylation and reduced SOD1 aggregation in a J-domain and ubiquitin interaction motif (UIM) dependent manner. PMID:21625540 The J-domain down-regulates the protein level of Atx3 through HSP70 mediated proteasomal degradation, while the UIM domain may alleviate this process via maintaining the ubiquitinated Atx3.
GO:0051082 unfolded protein binding	IDA PMID:24023695 Molecular chaperone mediated late-stage neuroprotection in t...	MODIFY	Summary: GO:0051082 (unfolded protein binding) is now formally obsolete (go-ontology#30962). This IDA annotation from Novoselov et al. (2013) is based on data showing that HSJ1a preferentially bound to mutant SOD1(G93A) and reduced SOD1 aggregation in a J-domain and UIM-dependent manner. The paper describes HSJ1a as acting through a combination of chaperone, co-chaperone, and pro-ubiquitylation activity (PMID:24023695). The data demonstrate that DNAJB2 functions as a protein folding chaperone that cooperates with HSP70 to actively prevent protein aggregation, rather than passively binding unfolded proteins. The replacement term GO:0044183 (protein folding chaperone) accurately captures this activity. Reason: GO:0051082 is now formally obsolete. The experimental evidence in Novoselov et al. (2013) shows that HSJ1a acts as a chaperone/co-chaperone that cooperates with HSP70 to reduce SOD1 aggregation via its J domain. The J domain mutant H31Q could still bind mutant SOD1 but non-productively, confirming this is active chaperone function rather than passive binding. GO:0044183 (protein folding chaperone) is the appropriate replacement. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:24023695 HSJ1a preferentially bound to mutant SOD1, enhanced SOD1 ubiquitylation and reduced SOD1 aggregation in a J-domain and ubiquitin interaction motif (UIM) dependent manner. Collectively, the data suggest that HSJ1a acts on mutant SOD1 through a combination of chaperone, co-chaperone and pro-ubiquitylation activity. PMID:24023695 The J domain mutant could still bind to mutant SOD1 but the binding appears to be non-productive and suggests that HSJ1a co-operates with Hsp70 to actively prevent mutant SOD1 aggregation, rather than by a passive chaperone action.
GO:0001671 ATPase activator activity	IDA PMID:7957263 Regulation of 70-kDa heat-shock-protein ATPase activity and ...	ACCEPT	Summary: Cheetham et al. (1994) directly demonstrated that HSJ1a and HSJ1b enhance the intrinsic ATPase activity of constitutive Hsc70 more than fivefold in vitro (PMID:7957263). This enhancement is mediated by an increase in the rate of bound ATP hydrolysis. This is a core molecular function of DNAJB2 as a J-domain co-chaperone. Reason: ATPase activator activity is directly demonstrated by in vitro assay showing more than fivefold stimulation of Hsc70 ATPase by HSJ1a and HSJ1b (PMID:7957263). This is the defining molecular function of J-domain co-chaperones. Supporting Evidence: PMID:7957263 The weak intrinsic ATPase activity of the constitutive 70-kDa heat-shock protein is enhanced more than fivefold by stoichiometric amounts of both HSJ1a and HSJ1b. This enhancement is mediated by an increase in the rate of bound ATP hydrolysis, whereas the rate of ADP release is unaffected.
GO:0032091 negative regulation of protein binding	IDA PMID:7957263 Regulation of 70-kDa heat-shock-protein ATPase activity and ...	KEEP AS NON CORE	Summary: Cheetham et al. (1994) showed that in the presence of ATP, HSJ1 proteins reduce Hsc70/ carboxymethylated alpha-lactalbumin complex formation, i.e., they reduce binding of Hsc70 to its substrate (PMID:7957263). The authors interpreted this as HSJ1 inducing a conformational change in Hsc70 that modulates substrate release. This is a mechanistic consequence of the J-domain-mediated ATPase cycle regulation, where HSJ1 drives HSP70 substrate turnover. While the observation is valid, GO:0032091 (negative regulation of protein binding) is a very generic biological process term that does not adequately capture the specific mechanism. Reason: The observation is valid but the term is very general. DNAJB2 modulates Hsc70 substrate binding as part of the ATPase cycle, driving substrate release. This is better understood as part of the co-chaperone mechanism (regulation of protein folding, ATPase activation) rather than as a standalone process. It is a mechanistic detail of the co-chaperone function. Supporting Evidence: PMID:7957263 In the presence of ATP, HSJ1 proteins reduce 70-kDa constitutive heat-shock protein/carboxymethylated alpha-lactalbumin complex formation both in the presence and absence of K+.
GO:0032781 positive regulation of ATP-dependent activity	IDA PMID:7957263 Regulation of 70-kDa heat-shock-protein ATPase activity and ...	ACCEPT	Summary: Cheetham et al. (1994) showed that HSJ1a and HSJ1b stimulate the ATP-dependent activity of Hsc70, enhancing its ATPase activity more than fivefold (PMID:7957263). Positive regulation of ATP-dependent activity is an appropriate biological process term that captures the downstream effect of the J-domain-mediated ATPase activation. Reason: This accurately describes the biological process resulting from DNAJB2's ATPase activator activity. HSJ1 proteins stimulate HSP70 ATP hydrolysis, thereby positively regulating ATP-dependent chaperone function (PMID:7957263). Supporting Evidence: PMID:7957263 The weak intrinsic ATPase activity of the constitutive 70-kDa heat-shock protein is enhanced more than fivefold by stoichiometric amounts of both HSJ1a and HSJ1b.
GO:1903332 regulation of protein folding	IDA PMID:7957263 Regulation of 70-kDa heat-shock-protein ATPase activity and ...	ACCEPT	Summary: Cheetham et al. (1994) demonstrated that HSJ1 proteins regulate Hsc70 ATPase activity and substrate binding, which are the key determinants of chaperone-mediated protein folding (PMID:7957263). By modulating the ATPase cycle and substrate release, HSJ1 proteins regulate the protein folding activity of Hsc70. This is an appropriate biological process annotation. Reason: Regulation of protein folding accurately captures the biological outcome of DNAJB2's co-chaperone activity. By stimulating Hsc70 ATPase and modulating substrate binding, DNAJB2 regulates the protein folding cycle (PMID:7957263). This is a core biological function. Supporting Evidence: PMID:7957263 HSJ1 proteins appear to regulate the affinity of the 70-kDa constitutive heat-shock protein for the permanently unfolded substrate, carboxymethylated alpha-lactalbumin.
GO:0001671 ATPase activator activity	IDA PMID:22219199 The C-terminal helices of heat shock protein 70 are essentia...	ACCEPT	Summary: Gao et al. (2012) confirmed that the J domain of HSJ1a mediates ATPase activation of HSP70, using NMR structural studies and in vitro assays (PMID:22219199). They showed the C-terminal helical subdomain of HSP70 is crucial for J-domain binding and ATPase stimulation, providing the structural basis for this core function. Reason: Independent confirmation of ATPase activator activity using structural and biochemical approaches (PMID:22219199). Corroborates the earlier findings of Cheetham et al. (1994). Supporting Evidence: PMID:22219199 The C-terminal helical alpha-subdomain of HSP70, which was considered to function as a lid of the substrate-binding domain, is crucial for binding with the J domain of HSJ1a and stimulating the ATPase activity of HSP70.
GO:0030544 Hsp70 protein binding	IPI PMID:22219199 The C-terminal helices of heat shock protein 70 are essentia...	ACCEPT	Summary: Gao et al. (2012) demonstrated the physical interaction between the J domain of HSJ1a and HSP70 using NMR titration and biochemical assays (PMID:22219199). The with/from column indicates P0DMV8 (HSPA1A). The paper characterized the structural determinants of this interaction, showing the C-terminal helices of HSP70 are essential for J-domain binding. Reason: Direct physical interaction between DNAJB2 J domain and HSP70 is demonstrated by NMR and biochemical studies (PMID:22219199). This is a core molecular function. Supporting Evidence: PMID:22219199 We studied the interaction between human-inducible HSP70 and Homo sapiens J-domain protein (HSJ1a), a J domain and UIM motif-containing co-chaperone.
GO:0032781 positive regulation of ATP-dependent activity	IDA PMID:22219199 The C-terminal helices of heat shock protein 70 are essentia...	ACCEPT	Summary: Gao et al. (2012) confirmed that the J domain of HSJ1a stimulates the ATPase activity of HSP70, providing the structural basis for this activation (PMID:22219199). This independent confirmation corroborates the earlier functional data from Cheetham et al. (1994). Reason: Independent confirmation of positive regulation of ATP-dependent activity by structural and biochemical studies (PMID:22219199). Supporting Evidence: PMID:22219199 The C-terminal helical alpha-subdomain of HSP70, which was considered to function as a lid of the substrate-binding domain, is crucial for binding with the J domain of HSJ1a and stimulating the ATPase activity of HSP70.
GO:0005634 nucleus	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	ACCEPT	Summary: Hageman et al. (2011) observed DNAJB2 in the nucleus by immunofluorescence as part of their systematic characterization of HSP70 machine components (PMID:21231916). UniProt confirms nuclear localization for isoform 2 (HSJ1a) based on PMID:12754272. The Ottaviani et al. (2017) paper also confirmed nuclear and cytosolic localization of HSJ1a in SK-N-SH neuronal cells (PMID:28031292). Reason: Nuclear localization is experimentally confirmed by IDA evidence (PMID:21231916) and corroborated by multiple studies (PMID:12754272, PMID:28031292). HSJ1a localizes to both cytoplasm and nucleus. Supporting Evidence: PMID:28031292 In all cases the HSJ1a signal was predominantly in the cytosol and nucleus, as previously reported (7).
GO:0005829 cytosol	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	ACCEPT	Summary: Hageman et al. (2011) observed cytosolic localization of DNAJB2 by immunofluorescence as part of their systematic HSP70 machine characterization (PMID:21231916). Multiple studies confirm that HSJ1a is predominantly cytosolic (PMID:12754272, PMID:28031292). Reason: Cytosol localization is experimentally confirmed by IDA evidence (PMID:21231916) and corroborated by multiple studies. HSJ1a is the cytosolic isoform of DNAJB2. Supporting Evidence: PMID:28031292 In all cases the HSJ1a signal was predominantly in the cytosol and nucleus, as previously reported (7).
GO:0042026 protein refolding	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	ACCEPT	Summary: Hageman et al. (2011) directly assessed protein refolding activity by measuring refolding of heat-denatured luciferase upon overexpression of HSP40/DNAJ family members including DNAJB2 (PMID:21231916). DNAJB2 showed distinct chaperone-like activities in this systematic study. Protein refolding is a core function of the HSP70/HSP40 chaperone machine. Reason: Protein refolding is directly demonstrated by IDA evidence from luciferase refolding assays (PMID:21231916). This is a core biological process for DNAJB2 as an HSP70 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. 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: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 now formally obsolete (go-ontology#30962). This IDA annotation from Hageman et al. (2011) is based on systematic characterization of HSP70 machine components. The paper assessed the effect of overexpression of HSP70 and HSP40/DNAJ family members on refolding of heat-denatured luciferase and suppression of polyQ aggregation, demonstrating that these are protein folding chaperones with distinct chaperone-like activities (PMID:21231916). DNAJB2 is part of the HSP70 chaperone machine, functioning as a J-protein co-chaperone that assists HSP70 in protein folding. The replacement term GO:0044183 (protein folding chaperone) accurately captures this function. Reason: GO:0051082 is now formally obsolete. Hageman et al. (2011) characterized DNAJB2 as part of the HSP70 machine with distinct chaperone-like activities including protein refolding and aggregation suppression. This is protein folding chaperone activity (GO:0044183), not standalone unfolded protein binding. The term GO:0044183 (protein folding chaperone) is the appropriate replacement. Proposed replacements: protein folding 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. 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. PMID:24023695 The molecular chaperone HSJ1 (DNAJB2) is a member of the Hsp40 (or DnaJ) family of heat shock proteins that contain a J domain, which is crucial in substrate recognition by Hsp70 [21], [22], [23]. Thus, Hsp40/DnaJ protein function is essential for Hsp70 function, including protein folding and directing misfolded proteins towards the proteasome [23].
GO:0090084 negative regulation of inclusion body assembly	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	ACCEPT	Summary: Hageman et al. (2011) demonstrated that DNAJB2 (and other HSP40/DNAJ family members) suppress aggregation of polyQ-expanded Huntingtin fragment, which forms inclusion bodies (PMID:21231916). Novoselov et al. (2013) showed HSJ1a reduced SOD1 inclusion formation in SK-N-SH cells in a J-domain and UIM-dependent manner (PMID:24023695). Negative regulation of inclusion body assembly is a well-characterized function of DNAJB2. Reason: Negative regulation of inclusion body assembly is directly demonstrated by IDA evidence showing suppression of polyQ aggregation (PMID:21231916) and SOD1 inclusion formation (PMID:24023695). This represents a key biological outcome of DNAJB2's combined chaperone and ubiquitin-binding activities. Supporting Evidence: PMID:24023695 The expression of HSJ1a led to a significant reduction in SOD1-G93A inclusions and redistribution to an even cytoplasmic and nuclear staining pattern similar to the SOD1-WT.
GO:0006986 response to unfolded protein	TAS PMID:1599432 Human homologues of the bacterial heat-shock protein DnaJ ar...	MARK AS OVER ANNOTATED	Summary: This TAS annotation from PINC references Cheetham et al. (1992), the original cloning paper for HSJ1/DNAJB2 (PMID:1599432). The paper identified HSJ1 as a human DnaJ homologue expressed preferentially in neurons, and noted the DnaJ-DnaK interaction is involved in protein folding and complex dissociation. The annotation to "response to unfolded protein" is appropriate as DNAJB2 is part of the chaperone response to misfolded/unfolded proteins. However, DNAJB2 is constitutively expressed and functions as a co-chaperone rather than being specifically induced as a stress response. The term is imprecise for DNAJB2's constitutive neuronal proteostasis role. Reason: While DNAJB2 is related to DnaJ stress response proteins and functions in protein quality control, "response to unfolded protein" implies a stress-responsive process. DNAJB2 is constitutively expressed in neurons (PMID:1599432) and functions in basal proteostasis. Its core functions are better captured by protein folding, protein refolding, and regulation of proteasomal degradation terms. The annotation overstates the stress-response aspect of the original cloning and homology evidence. Supporting Evidence: PMID:1599432 The bacterial heat-shock protein DnaJ has been implicated in protein folding and protein complex dissociation. The DnaJ protein interacts with the prokaryotic analogue of Hsp70, DnaK, and accelerates the rate of ATP hydrolysis by DnaK.

Gene Description

Existing Annotations Review

Core Functions

DNAJB2 stimulates the intrinsic ATPase activity of HSP70/Hsc70 more than fivefold via its J-domain. Both HSJ1a and HSJ1b isoforms enhance ATP hydrolysis by Hsc70, driving the chaperone cycle for substrate binding and release.

References

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