DNAJB6

Summary: Cytoplasmic pools include cytosol, a perinuclear pool and muscle Z discs.

Reason: The target sequence lies below the actual PTN002889875 IBD in PTHR43948. Human HPA data support cytosol, the curated 10954706 source supports a perinuclear pool, and 22366786 directly reports Z-disc staining. These nonredundant descendants refine the broad cytoplasm term without making any pool exclusive or assigning all four products the same distribution.

Proposed replacements: cytosol perinuclear region of cytoplasm Z disc

Summary: The inherited folding claim has a valid phylogenetic basis, but its precise functional interpretation remains unresolved.

Reason: The human target is demonstrably descended from PTN002889875; the current IBD is grounded in experimental human DNAJB6 and DNAJB8 annotations. Neither the target occurring as a donor nor the number of donors is a defect. However, GO:0006457 requires assistance in attaining correct tertiary structure. The inspected DNAJB6b luciferase assay in 21231916 is refolding-negative, while 23612975 principally measures aggregation suppression and client proximity. These do not falsify folding for every client, but they do not resolve the stricter folding claim. Preserve the positive ancestral assertion pending a substrate-specific productive-folding assay; do not equate all proteostasis with folding.

Summary: A supported nuclear pool can be specified as nucleoplasm.

Reason: The target descends from the actual PTN001940746 nuclear IBD. Independently inspected human HPA data and the literal O75190 Reactome nucleoplasmic participant support GO:0005654. This refinement does not assert that every natural product or every experimental construct is exclusively nucleoplasmic.

Proposed replacements: nucleoplasm

Summary: The demonstrated HSP70 interaction refines chaperone binding.

Reason: The PTN002889875 chaperone-binding IBD is on the target lineage and has experimental descendant grounding. DNAJB6-specific Hsp/c70 association and J-domain mapping in 10954706, together with purified J-domain binding in 37923706, support the descendant Hsp70 protein binding term. Binding is regulated: the GF region inhibits access in the tested WT constructs. Other positive co-complex associations are preserved separately and are not assumed to be binary recognition.

Proposed replacements: Hsp70 protein binding

Summary: The supported antiaggregation activity is represented by the proposed holdase chaperone activity term.

Reason: The current IBD at PTN002889875 and the target descendant path are verified. Its DNAJB8 experimental grounding is retained, including the actual 23612975 antiaggregation assays. Current GO:0044183 explicitly describes binding a client to assist folding. Antiaggregation and proximity do not alone demonstrate productive folding, and DNAJB6b did not improve luciferase refolding in 21231916. A single negative assay is not universal loss of ancestral folding activity, so neither removal nor a categorical non-folding claim is justified. The term-level interpretation remains uncertain. The unresolved ontology gap is distinct from uncertainty about the observed antiaggregation activity. The repository provides an explicit NTR route: use the proposed holdase chaperone activity for binding-dependent aggregation prevention without asserting productive folding or carrier delivery. This refinement does not claim loss of every possible ancestral folding activity.

Proposed replacements: holdase chaperone activity

Summary: The supported antiaggregation activity is represented by the proposed holdase chaperone activity term.

Reason: The historical IBA identifies PTN002889875, whose current lineage and related functional IBDs were reconstructed. Current QuickGO marks GO:0051082 obsolete and suggests activity-based replacements. GO:0044183 requires folding, whereas GO:0140309 requires keeping a client unfolded for delivery. The inspected target assays do not establish either productive folding or a delivery step. Preserve the historical source assertion and positive antiaggregation evidence while using a clearly proposed, rather than existing, molecular-function term. The unresolved ontology gap is distinct from uncertainty about the observed antiaggregation activity. The repository provides an explicit NTR route: use the proposed holdase chaperone activity for binding-dependent aggregation prevention without asserting productive folding or carrier delivery. This refinement does not claim loss of every possible ancestral folding activity.

Proposed replacements: holdase chaperone activity

Summary: The electronic nuclear annotation can be refined to the supported nucleoplasm.

Reason: The imported mapping names mouse O54946 and the UniProt nuclear location. The actual mouse-source study 16260608 includes human/mouse Mrj constructs and nuclear recruitment, while independent human HPA and Reactome data establish a nucleoplasmic pool. Use the supported descendant without claiming that the original mouse ChIP experiment measured every human product.

Proposed replacements: nucleoplasm

Summary: DNAJB6 localizes to muscle Z discs.

Reason: The UniProt location mapping SL-0314 is corroborated by actual 22366786 human muscle immunofluorescence: DNAJB6 was primarily at Z discs in control and affected samples, with control staining reported but not shown. Patient myofibrillar disintegration is a separate phenotype, not the sole localization evidence.

Summary: HSP70 binding is supported by target-specific experiments.

Reason: IPR043183 genuinely matches O75190 and its current GO mapping is Hsp70 protein binding. The target-specific 10954706 interaction and 37923706 purified J-domain NMR assay corroborate that mapping. This is a regulated binding capability, not a claim that all full-length WT protein is constitutively bound to HSP70.

Summary: A perinuclear cytoplasmic pool is supported.

Reason: The exact UniProt SL-0198 mapping agrees with the curated 10954706 localization and the official DNAJB6 record. The original full Methods were not recovered, so precise antibody/construct interpretation is deferred to the curator; this is not a nuclear-envelope-lumen assignment.

Summary: The supported antiaggregation activity is represented by the proposed holdase chaperone activity term.

Reason: The historical InterPro mapping is IPR043183, which matches the target; the current entry retains Hsp70 binding rather than this obsolete term. Current QuickGO marks GO:0051082 obsolete and suggests activity-based replacements. GO:0044183 requires folding, whereas GO:0140309 requires keeping a client unfolded for delivery. The inspected target assays do not establish either productive folding or a delivery step. Preserve the historical source assertion and positive antiaggregation evidence while using a clearly proposed, rather than existing, molecular-function term. The unresolved ontology gap is distinct from uncertainty about the observed antiaggregation activity. The repository provides an explicit NTR route: use the proposed holdase chaperone activity for binding-dependent aggregation prevention without asserting productive folding or carrier delivery. This refinement does not claim loss of every possible ancestral folding activity.

Proposed replacements: holdase chaperone activity

Summary: K18 and Hsp/c70 interactions provide informative binding functions.

Reason: The complete 10954706 abstract explicitly reports K18 and Hsp/c70 co-immunoprecipitation and maps the interactions to distinct DNAJB6 regions. Source-specific curated interaction records also retain KRT18 and HSPA8 pairs with tested fragments. Retain the supported intermediate-filament and Hsp70 binding refinements without claiming a purified affinity measurement from the inaccessible original Methods.

Proposed replacements: Hsp70 protein binding intermediate filament binding

Summary: The BRMS1 association is supported, without a distinct functional assignment.

Reason: Actual 16919237 Methods/Results report controlled human BRMS1 yeast two-hybrid screening and MRJ co-immunoprecipitation in COS7 cells. The positive source-specific Q9HCU9 pair is retained. The historical MRJ fragment differs from a simple current full-length isoform assignment, and neither metastasis regulation nor client-folding activity follows from the interaction alone. Keep the generic binding under the scoped project instruction.

Summary: Fragment-screen interactions with MLF1 and MLF2 are retained.

Reason: Literal 23414517 records join DNAJB6 to P58340/MLF1 and Q15773/MLF2 in the human muscle yeast two-hybrid study, with recorded DNAJB6 and partner fragments. Original Methods describe controlled reporter screening and sequence identification. These are positive binary-assay observations, not evidence that every pair was confirmed by the study's separate muscle PLA experiments or that the partners define a new DNAJB6 activity. Keep as non-core generic binding under the project instruction.

Summary: MLF1/MLF2 interactions in the chaperone network are supported.

Reason: The literal 25036637 records identify MLF1 and MLF2 in FLAG affinity and LUMIER assays. Actual Methods establish the human-expression assay and its controls; the source does not make these partners HSP70 or establish a new client-folding mechanism. Retain positive generic association as non-core under the project instruction.

Summary: The source-specific neurodegeneration interactome pairs are retained.

Reason: The ten literal source partners and all recorded sequence ROGIDs, including named partner splice products and tested fragments, were independently matched to official sequences. Actual 32814053 Methods describe reporter-controlled yeast two-hybrid screening; the separate mammalian validation protocol is not assumed to have validated every DNAJB6 pair. These positive screen interactions do not establish a shared physiological client mechanism, so retain generic binding as non-core under the project instruction.

Summary: The BioPlex MLF1 association is supported.

Reason: The literal 33961781 records identify DNAJB6–MLF1 in 293T and HCT116 affinity-purification experiments. The original Methods document sequence-validated human ORFs, C-terminal FLAG-HA tags and cell-line-specific network inference. These controlled associations do not by themselves establish direct molecular recognition or a specific new biological role. Retain non-core generic binding under the project instruction.

Summary: The U2OS AP-MS network contains the DNAJB6–MLF1 association.

Reason: The paper-linked primary AP-MS graph contains the exact DNAJB6 and MLF1 gene nodes connected by edge 579008. Actual 40205054 Methods describe U2OS expression of C-terminal FLAG-HA baits and stringent AP-MS filtering. This is source-specific positive evidence rather than transfer from older MLF1 studies; it supports association, not a purified direct-binding or functional-client claim. Keep non-core generic binding under the project instruction.

Summary: Promoter recruitment is supported, but assigning direct DNA binding overextends that evidence.

Reason: The imported donor is mouse O54946 and its source is PMID:16260608. The actual original includes mouse and human Mrj constructs, direct protein interaction with NFATc3 and HDAC4, and formaldehyde ChIP showing Mrj in an NFAT-associated TNF-promoter complex in rat cardiomyocytes. The Figure 6B EMSA asks whether Mrj blocks NFAT binding to DNA; it is not a direct Mrj–DNA affinity assay. The supported mechanism is recruitment through the transcription-factor/corepressor complex. Treating that promoter association as direct DNA binding is an over-annotation of the electronic transfer. This does not deny the positive promoter association or assert that direct Mrj–DNA contact is impossible.

Summary: The inherited cytoplasmic annotation can be refined to established human pools.

Reason: The O54946 donor is a genuine ortholog with experimentally supported cytoplasmic distribution. Independent human data identify cytosol, a perinuclear pool and Z discs. These supported descendants replace the broad term while keeping the mouse-source and human corroboration distinct; none is an exclusive localization for all products.

Proposed replacements: cytosol perinuclear region of cytoplasm Z disc

Summary: Human HPA data support a nucleoplasmic pool.

Reason: The inspected HPA target record matches ENSG00000105993/O75190 and reports supported nucleoplasm localization by ICC/IF. The data record, not independent microscopy-pixel interpretation, was reviewed. It does not resolve the four natural products individually; the literal Reactome nucleoplasmic participant provides separate corroboration.

Summary: Human HPA data support a cytosolic pool.

Reason: The inspected HPA target record reports supported cytosol localization alongside nucleoplasm. This agrees with DNAJB6b functional/localization studies while leaving the HPA signal itself product-unresolved.

Summary: Heat-response regulation is a supported pathway context.

Reason: The actual Reactome pathway contains the nucleoplasmic and cytosolic HSP70 ATP-hydrolysis events, with O75190 explicitly in the co-chaperone catalyst sets. The 21231916 cellular experiments independently show protection against heat-induced luciferase aggregation. This supports a contextual heat response rather than a separate DNAJB6 heat-sensing mechanism or autonomous HSF1 regulation.

Summary: The nervous-system process assertion cannot be fully adjudicated from the accessible source.

Reason: The complete 11896048 abstract reports brain enrichment and suppression of polyglutamine aggregation, caspase activity and toxicity. Those observations are real, but the full original experiment was not recovered and its nervous-system-process scope remains unresolved. Do not infer that the curator annotated expression alone or that the unseen paper lacks a relevant neural assay.

Summary: ATPase activation is retained as a conditional J-domain capability.

Reason: The actual Reactome:R-HSA-5251955 catalyst path contains O75190 in the nucleoplasm co-chaperone set. Direct 37923706 phosphate-release experiments show activation by the exposed DNAJB6 J-domain, whereas full-length WT and WT JD-GF are autoinhibited under those conditions. Retain the curated capability without implying constitutive full-length stimulation, measured native release of inhibition, or activity of all natural splice products. The exposed-domain and pathogenic-mutant measurements establish a biochemical capability, while the physiological release mechanism in intact WT remains unmeasured. Retain this positive capability as non-core; the core records the independently supported HSP70 interaction rather than constitutive ATPase activation by intact WT.

Summary: ATPase activation is retained as a conditional J-domain capability.

Reason: The actual Reactome:R-HSA-5251959 catalyst path contains O75190 in the cytosol co-chaperone set. Direct 37923706 phosphate-release experiments show activation by the exposed DNAJB6 J-domain, whereas full-length WT and WT JD-GF are autoinhibited under those conditions. Retain the curated capability without implying constitutive full-length stimulation, measured native release of inhibition, or activity of all natural splice products. The exposed-domain and pathogenic-mutant measurements establish a biochemical capability, while the physiological release mechanism in intact WT remains unmeasured. Retain this positive capability as non-core; the core records the independently supported HSP70 interaction rather than constitutive ATPase activation by intact WT.

Summary: The HSP70-family interaction is more informative than generic chaperone binding.

Reason: The source annotation names HSP70-family partners. The independently inspected 21231916 DNAJB6b cellular panels support its chaperone context; that paper's purified ATPase/refolding section instead uses DNAJB1 and is not a DNAJB6 assay. Target-specific Hsp/c70 interaction in 10954706 and purified J-domain recognition in 37923706 corroborate the Hsp70-binding refinement, with the original curated interaction retained.

Proposed replacements: Hsp70 protein binding

Summary: DNAJB6 improves localization of an aggregation-prone Parkin variant in the tested cells.

Reason: Actual 20889486 Results/Figure 3 report partial rescue of Parkin C289G relocation to damaged mitochondria after DNAJB6 expression. This is a source-specific localization effect. The paper's stronger LC3/clearance and J-domain experiments largely concern HSJ1a, so no general DNAJB6 mitophagy, transport or restored native-fold mechanism is inferred.

Summary: Inhibition of inclusion formation is a central DNAJB6 function.

Reason: The 20889486 source describes reduced mutant-Parkin aggregation after DNAJB6 expression, with the aggregation observation discussed as data not shown and the relocation assay shown separately. Independent target-specific polyQ aggregation experiments in 20159555, 21231916, 22366786 and 37923706 establish the broader antiaggregation activity. Retain the annotation without transferring HSJ1a-specific clearance mechanisms.

Summary: Membrane association remains unresolved from the accessible target evidence.

Reason: GO:0016020 includes attached proteins and does not require a transmembrane helix. The complete 19946888 abstract describes YTS membrane enrichment and explicitly allows nonintegral association. The target-specific table/fraction assignment and full controls could not be independently recovered. Therefore the old contamination-based removal is unjustified, but a defined DNAJB6 membrane pool is not established by the accessible record alone.

Summary: The nuclear localization claim can be refined to independently supported nucleoplasm.

Reason: The source's DNAJB6 experiments must be kept distinct from unrelated chaperone panels and from an automatic modern isoform-A assignment. The gene-level nuclear observation is corroborated by supported human HPA nucleoplasm data and the literal Reactome O75190 nucleoplasmic participant. Use that descendant without asserting exclusive nuclear localization or exact historical construct mapping.

Proposed replacements: nucleoplasm

Summary: A cytosolic DNAJB6 pool is supported.

Reason: The actual 21231916 DNAJB6b cellular experiments and product-localization context support cytosol, independently corroborated by human HPA. The tested b construct is not evidence that all four current natural products share its distribution or activity.

Summary: The supported antiaggregation activity is represented by the proposed holdase chaperone activity term.

Reason: The source-specific 21231916 experiments show DNAJB6b suppression of polyQ and heat-induced luciferase aggregation, but no improvement of luciferase refolding. Current QuickGO marks GO:0051082 obsolete and suggests activity-based replacements. GO:0044183 requires folding, whereas GO:0140309 requires keeping a client unfolded for delivery. The inspected target assays do not establish either productive folding or a delivery step. Preserve the historical source assertion and positive antiaggregation evidence while using a clearly proposed, rather than existing, molecular-function term. The unresolved ontology gap is distinct from uncertainty about the observed antiaggregation activity. The repository provides an explicit NTR route: use the proposed holdase chaperone activity for binding-dependent aggregation prevention without asserting productive folding or carrier delivery. This refinement does not claim loss of every possible ancestral folding activity.

Proposed replacements: holdase chaperone activity

Summary: DNAJB6b suppresses inclusion formation in direct cellular assays.

Reason: The actual 21231916 DNAJB6b panels demonstrate suppression of HDQ74 and heat-induced luciferase aggregation. The same paper's failure to improve luciferase refolding distinguishes this positive antiaggregation function from productive folding; it does not negate the inclusion-body annotation.

Summary: The curated sperm-nuclear detection is retained at its measured broad compartment.

Reason: The complete 21630459 abstract describes highly purified human sperm nuclei, but the DNAJB6 target table was not independently recovered. Nuclear localization is independently established for the gene, so the positive HDA annotation is retained with curator deference. Do not replace this source-specific sperm-nuclear pool with an unmeasured nucleoplasm or chromatin subfraction merely because somatic HPA supports nucleoplasm.

Summary: Reactome explicitly places the DNAJB6 participant in nucleoplasm.

Reason: The inspected catalyst-to-defined-set-to-O75190 path reaches the DNAJB6 2–326 nucleoplasmic entity. This is a curated model supported by independent human HPA localization, not a new measurement of every splice product or of constitutive HSP70 stimulation in nuclei.

Summary: Reactome explicitly places the DNAJB6 participant in cytosol.

Reason: The inspected catalyst-to-defined-set-to-O75190 path reaches the DNAJB6 2–326 cytosolic entity. This is a curated compartment model, independently consistent with human HPA and DNAJB6b experiments; the modeled sequence must not be silently relabeled as the 241-residue b construct.

Summary: The BAG3, HSPB8 and STUB1 associations are retained.

Reason: Actual 22366786 assays show DNAJB6b co-immunoprecipitation with these proteins in COS1 cells and contextual proximity in muscle. The curated source partners are exact. These findings do not by themselves resolve direct binary recognition of each partner or make every partner a folding chaperone. Retain positive generic binding under the project instruction rather than forcing one class-specific term over the whole set.

Summary: Human muscle experiments support Z-disc localization.

Reason: Actual 22366786 immunofluorescence reports DNAJB6 primarily in Z discs in control and affected human muscle. Patient Z-disc disruption and aggregates provide pathological context but are not substituted for normal localization. No stable CASA-complex membership or single-isoform localization is inferred from these images alone.

Summary: Hsp/c70 binding supports the specific HSP70-family term.

Reason: The complete 10954706 abstract and exact curated HSPA8 interaction distinguish the target from a generic heat-shock-protein class. GO:0030544 is a verified descendant of heat shock protein binding, and purified J-domain recognition is independently supported in 37923706.

Proposed replacements: Hsp70 protein binding

Summary: The nuclear fusion-protein observation is compatible with a nucleoplasmic pool.

Reason: Retain the imported fusion-localization assertion and use independent human HPA and Reactome evidence for the supported nucleoplasm refinement. The GO reference does not identify a modern splice-product sequence by itself, so no isoform field or universal localization is invented.

Proposed replacements: nucleoplasm

Summary: ATPase activation is retained as a conditional J-domain capability.

Reason: The 11896048 full original remains unavailable, so the earlier assertion that it lacks an ATPase assay is withdrawn. Independently, 37923706 directly measures activation by the exposed DNAJB6 J-domain and autoinhibition of tested full-length WT protein. This establishes a regulated target capability while preserving the older IDA source and its unresolved detailed assay scope. The exposed-domain and pathogenic-mutant measurements establish a biochemical capability, while the physiological release mechanism in intact WT remains unmeasured. Retain this positive capability as non-core; the core records the independently supported HSP70 interaction rather than constitutive ATPase activation by intact WT.

Summary: The nuclear observation is refined using independent nucleoplasmic evidence.

Reason: The curated 10954706 nuclear localization is retained without inventing its inaccessible Methods. Human HPA and the literal Reactome participant independently support nucleoplasm, a descendant of nucleus. This is a gene-level refinement, not proof that the original antibody or every natural product specifically measured that subcompartment.

Proposed replacements: nucleoplasm

Summary: The productive-folding interpretation of the original IDA remains unresolved.

Reason: The complete 11896048 abstract establishes polyQ antiaggregation and protection from toxicity, but the full experiment is unavailable. Current GO:0006457 is specifically assistance in attaining correct tertiary structure; neither abstract silence nor a later luciferase-negative assay can establish that the curator was wrong. Preserve the experimental assertion while leaving its folding-versus-antiaggregation scope undecided.

Summary: DNAJB6 contributes to keratin intermediate-filament organization.

Reason: The complete 10954706 abstract reports interaction with K18, colocalization with K8/18 filaments in HeLa cells and selective disruption of that network following anti-Mrj antibody injection, without comparable actin or microtubule disruption. This supports performed organization of the keratin network, with detailed original Methods still unavailable.

Summary: The perinuclear cytoplasmic annotation is retained.

Reason: The original curated localization and official UniProt record support the perinuclear pool. The 10954706 full Methods could not be recovered, so exact construct or antibody interpretation remains source-limited; no contradictory evidence warrants rejection.

Summary: The supported HSP70 interaction provides a specific chaperone-binding refinement.

Reason: Retain the 11896048 curator assertion without claiming its unavailable full Methods were inspected. Independent DNAJB6-specific evidence in 10954706 and purified J-domain recognition in 37923706 establish Hsp70 protein binding. The refinement describes regulated partner recognition and does not imply productive folding or constitutive full-length stimulation.

Proposed replacements: Hsp70 protein binding