id: O75190
gene_symbol: DNAJB6
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  DNAJB6 (also known as MRJ/HSJ-2) is a class B Hsp40/J-domain protein (JDP) co-chaperone that stimulates the ATPase activity
  of Hsp70 family members and acts as a potent suppressor of amyloid-type protein aggregation. Unlike canonical foldase
  chaperones, DNAJB6 does not refold denatured proteins but instead exhibits holdase-like activity, preventing aggregation
  of polyglutamine-expanded proteins, tau, and other aggregation-prone substrates. It functions within the Hsp70 chaperone
  network, requiring its J-domain for anti-aggregation activity. DNAJB6 also plays roles in keratin filament organization
  and nuclear pore complex assembly quality control. Mutations in DNAJB6 cause limb-girdle muscular dystrophy type D1
  (LGMDD1). Two major isoforms exist: DNAJB6a (long, predominantly nuclear) and DNAJB6b (short, largely cytosolic),
  with isoform B being particularly important for suppression of protein aggregation.
alternative_products:
- name: A
  id: O75190-1
- name: B
  id: O75190-2
  sequence_note: VSP_001289, VSP_001290
- name: C (a)
  id: O75190-3
  sequence_note: VSP_026180
- name: D
  id: O75190-4
  sequence_note: VSP_053894
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      DNAJB6 localizes to the cytoplasm, particularly the DNAJB6b isoform which is predominantly cytosolic.
      This is well supported by multiple lines of evidence including immunostaining in PMID:10954706, subcellular
      fractionation in PMID:21231916, and the observation in PMID:22366786 that LGMD1D mutations exert their
      pathogenic effect specifically through the cytoplasmic isoform DNAJB6b. The IBA annotation is appropriately
      broad and well supported by phylogenetic conservation.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is a well-established core feature of DNAJB6, especially the DNAJB6b isoform.
      PMID:10954706 showed colocalization with K8/18 filaments in HeLa cells. PMID:21231916 demonstrated
      cytosolic localization by IDA. PMID:22366786 showed LGMD1D mutations exert effects through the
      cytoplasmic isoform specifically. The IBA annotation is correct and represents a core localization.
    supported_by:
      - reference_id: PMID:10954706
        supporting_text: >-
          Immunostaining with anti-Mrj antibody showed that Mrj colocalized with K8/18 filaments in HeLa cells.
      - reference_id: PMID:22366786
        supporting_text: >-
          Strikingly, these phenotypes were generated exclusively upon injection of mutant DNAJB6b;
          neither mutation, when engineered into DNAJB6a, had any impact (Fig. 2).
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      DNAJB6 is a DnaJ co-chaperone that participates in the Hsp70 chaperone network, which broadly functions
      in protein folding and quality control. However, DNAJB6 specifically acts as a holdase rather than a
      foldase -- it suppresses aggregation but cannot stimulate refolding of denatured substrates (PMID:21231916).
      The IBA annotation to GO:0006457 (protein folding) captures the general chaperone pathway context but
      is somewhat misleading for DNAJB6 specifically, since the protein prevents aggregation rather than
      promoting productive folding. However, protein folding as a GO BP term encompasses the broader
      process including aggregation prevention, so the term is acceptable if understood in this context.
    action: ACCEPT
    reason: >-
      While DNAJB6 is specifically a holdase rather than foldase (PMID:21231916), GO:0006457 (protein folding)
      as a biological process broadly encompasses protein quality control activities including aggregation
      prevention. DNAJB6 participates in the Hsp70-dependent protein folding/quality control pathway via
      its J-domain, and as an IBA annotation this represents a reasonable phylogenetically inferred function
      for the DnaJ family. The term is not wrong, though it should be understood that DNAJB6 contributes
      specifically to the anti-aggregation arm of protein quality control.
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          Overexpressed chaperones that suppressed polyQ aggregation were found not to be able to stimulate
          luciferase refolding.
      - reference_id: PMID:11896048
        supporting_text: >-
          overexpressed MRJ effectively suppressed polyglutamine-dependent protein aggregation, caspase
          activity, and cellular toxicity
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      DNAJB6 localizes to the nucleus, particularly the DNAJB6a isoform which is predominantly nuclear
      (PMID:10954706, PMID:22366786). PMID:10954706 showed nuclear localization by immunostaining.
      The deep research review also confirms nuclear localization for isoform A. The IBA annotation
      is well supported and phylogenetically appropriate for the DnaJ family.
    action: ACCEPT
    reason: >-
      Nuclear localization is well established for DNAJB6, particularly isoform A. PMID:10954706 demonstrated
      nuclear staining. This is a core localization for the protein, consistent with phylogenetic inference.
    supported_by:
      - reference_id: PMID:10954706
        supporting_text: >-
          Immunostaining with anti-Mrj antibody showed that Mrj colocalized with K8/18 filaments in HeLa cells.
          Mrj was immunoprecipitated not only with K18, but also with the stress-induced and constitutively
          expressed heat shock protein Hsp/c70.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      DNAJB6 binds Hsp70/HSPA family chaperones through its J-domain. PMID:10954706 demonstrated that
      Mrj (DNAJB6) immunoprecipitated with Hsp/c70 and that the N-terminal J-domain region mediates
      Hsp70 interaction. PMID:22366786 confirmed interaction with HSPA8 (Hsc70). The IBA annotation
      correctly reflects this core co-chaperone binding activity.
    action: ACCEPT
    reason: >-
      Binding to Hsp70 chaperones is the defining molecular function of J-domain proteins. DNAJB6
      interacts with Hsp/c70 via its J-domain (PMID:10954706), and this interaction is essential for
      the protein's co-chaperone function. The IBA annotation is a core function well supported
      by phylogenetic conservation across the DnaJ family.
    supported_by:
      - reference_id: PMID:10954706
        supporting_text: >-
          Mrj was immunoprecipitated not only with K18, but also with the stress-induced and constitutively
          expressed heat shock protein Hsp/c70. Mrj bound to K18 through its C terminus and interacted with
          Hsp/c70 via its N terminus, which contains the J domain.
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0044183 (protein folding chaperone) is an MF term describing proteins that bind other proteins to
      assist the protein folding process. DNAJB6 acts as a co-chaperone within the Hsp70 network, functioning
      specifically as a holdase that prevents aggregation rather than assisting productive folding. The IBA
      annotation is phylogenetically appropriate for the DnaJ family and represents the closest available
      GO molecular function term for DNAJB6 chaperone activity, even though a holdase-specific term would
      be more precise.
    action: ACCEPT
    reason: >-
      GO:0044183 is the best available MF term for DNAJB6 chaperone activity. While DNAJB6 specifically
      acts as a holdase rather than foldase (PMID:21231916), there is no dedicated holdase term in GO.
      The IBA annotation is phylogenetically sound for the DnaJ family. This is already being used as
      the replacement term for the obsoleting GO:0051082, making it a core annotation.
    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: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). DNAJB6 does bind unfolded/misfolded
      proteins as a co-chaperone, but crucially it does NOT refold them. PMID:21231916 demonstrated that DNAJB6
      suppresses polyQ aggregation but cannot stimulate luciferase refolding, indicating holdase-like rather than
      foldase activity. The IBA annotation propagated from phylogenetic inference is broadly correct in that DNAJB6
      engages unfolded clients, but the term itself is being obsoleted. GO:0044183 (protein folding chaperone) is the
      closest available replacement, though its definition ("Binding to a protein or a protein-containing complex to
      assist the protein folding process") is not ideal for a holdase. A dedicated holdase activity term would be more
      appropriate for DNAJB6 but does not currently exist in GO.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted per go-ontology#30962. DNAJB6 does interact with unfolded/aggregation-prone
      proteins, but its mechanism is holdase-like (preventing aggregation) rather than foldase-like (promoting
      refolding). PMID:21231916 showed that DNAJB6 overexpression suppressed polyQ aggregation but did not stimulate
      luciferase refolding. GO:0044183 (protein folding chaperone) is proposed as an interim replacement since it is
      the parent term already assigned by IBA, but a more specific holdase-type term would better capture DNAJB6
      function if one existed in GO.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    additional_reference_ids:
      - PMID:21231916
      - PMID:20159555
    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:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      This IEA annotation from Ensembl Compara ortholog transfer is consistent with the well-established
      nuclear localization of DNAJB6, particularly isoform A. Multiple experimental studies confirm
      nuclear localization (PMID:10954706, PMID:21231916, PMID:21630459). The IEA is broader than
      the IBA and IDA annotations but is not incorrect.
    action: ACCEPT
    reason: >-
      Nuclear localization is well supported experimentally. The IEA annotation is redundant with
      stronger IBA and IDA evidence but is not wrong. Accepted as a valid additional annotation.
    supported_by:
      - reference_id: PMID:10954706
        supporting_text: >-
          Immunostaining with anti-Mrj antibody showed that Mrj colocalized with K8/18 filaments in HeLa cells.
- term:
    id: GO:0030018
    label: Z disc
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      This IEA annotation from UniProtKB subcellular location mapping is supported by direct experimental
      evidence in PMID:22366786, which demonstrated by immunofluorescence that DNAJB6 localizes primarily
      to Z-disks in skeletal muscle. This localization is functionally relevant as LGMDD1 mutations
      cause Z-disk myofibrillar disintegration.
    action: ACCEPT
    reason: >-
      Z disc localization is directly demonstrated by IDA in PMID:22366786. The IEA annotation
      is consistent with this experimental evidence and correctly maps the UniProt subcellular
      location annotation.
    supported_by:
      - reference_id: PMID:22366786
        supporting_text: >-
          Immunofluorescence (IF) microscopy showed DNAJB6 primarily in Z-disks in both control
          (not shown) and LGMD1D muscle samples (Fig. 1a).
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      This IEA annotation from InterPro domain mapping correctly identifies DNAJB6 as an Hsp70-binding
      protein. DNAJB6 interacts with Hsp70/Hsc70 through its J-domain, as demonstrated experimentally
      in PMID:10954706 (co-immunoprecipitation with Hsp/c70) and confirmed by the Reactome pathway
      annotations (R-HSA-5251955, R-HSA-5251959). This is a core molecular function.
    action: ACCEPT
    reason: >-
      Hsp70 binding is the fundamental co-chaperone activity of all J-domain proteins. DNAJB6
      binds Hsp/c70 via its N-terminal J-domain (PMID:10954706). The InterPro mapping is accurate.
      While GO:0051087 (protein-folding chaperone binding) is a parent term also annotated, GO:0030544
      is more specific to the Hsp70 interaction and is a valid annotation.
    supported_by:
      - reference_id: PMID:10954706
        supporting_text: >-
          Mrj was immunoprecipitated not only with K18, but also with the stress-induced and constitutively
          expressed heat shock protein Hsp/c70. Mrj bound to K18 through its C terminus and interacted with
          Hsp/c70 via its N terminus, which contains the J domain.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      This IEA annotation from UniProtKB subcellular location mapping is consistent with the
      experimentally determined perinuclear localization of DNAJB6. PMID:10954706 demonstrated
      perinuclear staining by IDA, and the UniProt entry explicitly states perinuclear region
      localization (ECO:0000269|PubMed:10954706).
    action: ACCEPT
    reason: >-
      Perinuclear localization is experimentally supported by PMID:10954706 with IDA evidence.
      The IEA mapping from UniProt subcellular location vocabulary is correct and consistent
      with the direct experimental observation.
    supported_by:
      - reference_id: PMID:10954706
        supporting_text: >-
          Immunostaining with anti-Mrj antibody showed that Mrj colocalized with K8/18 filaments in HeLa cells.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      This IEA annotation was inferred from InterPro domain mapping (IPR043183, DNJB2/6-like). GO:0051082 is being
      obsoleted (go-ontology#30962). While the InterPro domain is correctly identified, the mapped term does not
      accurately capture DNAJB6 function. DNAJB6 has holdase-like activity (suppressing aggregation) rather than
      foldase activity (refolding proteins), as demonstrated in PMID:21231916. GO:0044183 (protein folding chaperone)
      is the closest available replacement term, though a holdase-specific term would be more appropriate.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted per go-ontology#30962. The IEA mapping from InterPro IPR043183 correctly
      identifies DNAJB6 as a J-domain protein that interacts with unfolded clients, but the term itself is being
      retired. DNAJB6 functions as a holdase rather than a foldase (PMID:21231916), so GO:0044183 (protein folding
      chaperone) is proposed as an interim replacement, acknowledging that a holdase-specific term would better
      represent the actual molecular activity.
    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:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10954706
  review:
    summary: >-
      PMID:10954706 demonstrated that DNAJB6 (Mrj) binds to K18 (keratin 18) and Hsp/c70 by
      yeast two-hybrid and co-immunoprecipitation. These are specific, functionally relevant
      interactions. However, GO:0005515 (protein binding) is an uninformative term that does not
      capture the nature of the interaction. More specific terms like GO:0030544 (Hsp70 protein
      binding) and GO:0045098 (type II intermediate filament binding) would better describe
      the interactions demonstrated.
    action: MODIFY
    reason: >-
      GO:0005515 (protein binding) is too vague and uninformative. The interactions demonstrated in
      PMID:10954706 -- with K18 and Hsp/c70 -- are specific and functionally relevant. These are
      better captured by GO:0030544 (Hsp70 protein binding) for the Hsp70 interaction and
      GO:0045098 (type II intermediate filament binding) for the K18 interaction.
    proposed_replacement_terms:
      - id: GO:0030544
        label: Hsp70 protein binding
      - id: GO:0045098
        label: type II intermediate filament binding
    supported_by:
      - reference_id: PMID:10954706
        supporting_text: >-
          Mrj was immunoprecipitated not only with K18, but also with the stress-induced and constitutively
          expressed heat shock protein Hsp/c70. Mrj bound to K18 through its C terminus and interacted with
          Hsp/c70 via its N terminus, which contains the J domain.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16919237
  review:
    summary: >-
      PMID:16919237 concerns the stabilization of BRMS1 by the Hsp90 chaperone system. DNAJB6 is listed
      as a binding partner from co-immunoprecipitation. The UniProt interaction data confirms BRMS1 (Q9HCU9)
      interacts with DNAJB6 (NbExp=2). This is likely a client or co-chaperone network interaction.
      GO:0005515 (protein binding) is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While the interaction with BRMS1 may be genuine from co-immunoprecipitation data, GO:0005515
      (protein binding) is an uninformative term. The interaction with BRMS1 is likely part of
      DNAJB6's general chaperone client handling rather than a specific functional interaction.
      This does not add meaningful information beyond what is already captured by more specific
      chaperone-related MF terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23414517
  review:
    summary: >-
      PMID:23414517 describes a human skeletal muscle interactome centered on proteins involved in
      muscular dystrophies. This is a large-scale interaction study. GO:0005515 (protein binding)
      from a high-throughput interactome study is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 (protein binding) from a large-scale interactome mapping study adds no
      specific functional information. The interactions detected in PMID:23414517 may be
      biologically relevant but the GO term itself is too general to be useful.
- 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. This is a systematic
      chaperone interactome study. GO:0005515 (protein binding) from this study is uninformative,
      though the underlying data about chaperone network interactions is valuable.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 (protein binding) from a systematic chaperone network study is too general.
      The chaperone-specific interactions are better captured by terms like GO:0051087
      (protein-folding chaperone binding) and GO:0030544 (Hsp70 protein binding), which
      are already annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: >-
      PMID:32814053 describes interactome mapping of neurodegenerative disease proteins. This is
      a high-throughput study. GO:0005515 (protein binding) is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 (protein binding) from a large-scale neurodegenerative disease interactome
      mapping study is too general to be informative. The chaperone-client interactions
      are better represented by more specific functional terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      PMID:33961781 describes dual proteome-scale networks revealing cell-specific remodeling of
      the human interactome. This is a high-throughput study. GO:0005515 (protein binding) is
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 (protein binding) from a large-scale proteomics interactome study is too
      general to be informative for understanding DNAJB6 function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: >-
      PMID:40205054 describes multimodal cell maps as a foundation for structural and functional genomics.
      This is a high-throughput study. GO:0005515 (protein binding) is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 (protein binding) from a large-scale cell map study is too general to be
      informative for DNAJB6 functional annotation.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      This IEA annotation from Ensembl Compara ortholog transfer suggests DNA binding activity.
      There is no direct experimental evidence for DNAJB6 binding DNA. DNAJB6 is a DnaJ co-chaperone
      with well-characterized protein-binding activities (Hsp70, keratin, aggregation-prone substrates)
      but no known nucleic acid binding activity. The J-domain and G/F-rich regions are protein interaction
      domains. While DNAJB6a localizes to the nucleus, this reflects its role in nuclear proteostasis
      rather than DNA binding. This annotation likely results from incorrect ortholog transfer.
    action: REMOVE
    reason: >-
      There is no experimental evidence for DNAJB6 DNA binding activity. DNAJB6 is a protein
      chaperone that interacts with Hsp70, keratins, and aggregation-prone substrates.
      Its nuclear localization (isoform A) relates to proteostasis functions, not DNA binding.
      This IEA annotation likely results from erroneous ortholog transfer and is not supported
      by any published literature or UniProt functional annotation. The UniProt entry describes
      only protein-protein interactions and chaperone activity, with no mention of DNA binding.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      This IEA annotation from Ensembl Compara ortholog transfer is consistent with the
      well-established cytoplasmic localization of DNAJB6, particularly isoform B. Redundant
      with the IBA annotation but not incorrect.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is well established for DNAJB6, especially isoform B. The IEA
      from ortholog transfer is consistent with direct experimental evidence and IBA annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      This IDA annotation from immunofluorescence curation (HPA) indicates nucleoplasm localization.
      DNAJB6a is predominantly nuclear. The Human Protein Atlas immunofluorescence data provides
      direct observation of nucleoplasmic localization, consistent with isoform A distribution
      and the Reactome pathway annotation R-HSA-5251955 (HSP40s activate HSP70 ATPase in nucleoplasm).
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is consistent with the known nuclear distribution of DNAJB6a.
      HPA immunofluorescence data provides direct visualization. This is supported by the
      Reactome pathway R-HSA-5251955 which places DNAJB6 in the nucleoplasm for HSP70 ATPase
      activation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      This IDA annotation from immunofluorescence curation (HPA) indicates cytosol localization.
      DNAJB6b is predominantly cytosolic. The Human Protein Atlas data is consistent with multiple
      studies showing cytosolic localization of DNAJB6b (PMID:21231916, PMID:22366786).
    action: ACCEPT
    reason: >-
      Cytosol localization is well established for DNAJB6b. HPA immunofluorescence provides
      direct evidence. Consistent with PMID:21231916 and PMID:22366786 which demonstrate
      cytosolic DNAJB6b function.
- term:
    id: GO:1900034
    label: regulation of cellular response to heat
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371453
  review:
    summary: >-
      This TAS annotation from Reactome (R-HSA-3371453, Regulation of HSF1-mediated heat shock response)
      places DNAJB6 in the heat shock response pathway. As a DnaJ/Hsp40 co-chaperone, DNAJB6
      participates in the Hsp70 chaperone network that is central to the cellular heat shock response.
      The Reactome pathway describes how chaperones regulate HSF1 activity. This is a legitimate
      biological process for DNAJB6 but represents a broader pathway context rather than a core
      specific function.
    action: KEEP_AS_NON_CORE
    reason: >-
      DNAJB6 participates in the Hsp70 chaperone network that regulates the heat shock response,
      but this represents a general pathway context rather than the specific anti-aggregation
      holdase activity that is DNAJB6's primary function. The Reactome pathway annotation is
      valid but non-core.
- term:
    id: GO:0050877
    label: nervous system process
  evidence_type: IDA
  original_reference_id: PMID:11896048
  review:
    summary: >-
      PMID:11896048 (Chuang et al. 2002) characterized DNAJB6/MRJ as a brain-enriched chaperone
      that inhibits Huntingtin aggregation. The paper showed that MRJ is highly enriched in the
      central nervous system and suppressed polyglutamine-dependent aggregation and toxicity in
      neuronal cell models. However, the annotation to GO:0050877 (nervous system process) is
      overly broad and not directly demonstrated. The paper shows DNAJB6 has chaperone activity
      that is relevant in neurons, but it does not demonstrate involvement in a specific nervous
      system process. The enrichment in brain and activity in neuronal cells does not constitute
      evidence for involvement in nervous system processes per se -- the chaperone activity is
      a general proteostasis function that happens to be important in neurons.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      PMID:11896048 demonstrates that DNAJB6 is brain-enriched and suppresses polyglutamine
      aggregation in neuronal cells, but this does not constitute direct evidence for involvement
      in nervous system processes. The chaperone/anti-aggregation activity is a general proteostasis
      function, not a nervous system-specific process. Being enriched in brain tissue does not make
      a protein's function a "nervous system process." The anti-aggregation activity is better
      captured by GO:0090084 (negative regulation of inclusion body assembly) and GO:0006457
      (protein folding).
    supported_by:
      - reference_id: PMID:11896048
        supporting_text: >-
          Tissue distribution studies showed that MRJ is highly enriched in the central nervous system.
          In an in vitro cell model of HD, overexpressed MRJ effectively suppressed polyglutamine-dependent
          protein aggregation, caspase activity, and cellular toxicity.
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5251955
  review:
    summary: >-
      This TAS annotation from Reactome (R-HSA-5251955, HSP40s activate intrinsic ATPase activity
      of HSP70s in the nucleoplasm) correctly identifies DNAJB6 as an activator of HSP70 ATPase
      activity. The Reactome pathway summary explicitly lists DNAJB6 (as DNAJB6) among the HSP40s
      that stimulate HSP70 ATPase activity, citing Izawa et al. 2000 (PMID:10954706) and Hanai &
      Mashima 2003. This is a core molecular function of all J-domain proteins.
    action: ACCEPT
    reason: >-
      ATPase activator activity toward Hsp70 is the defining molecular function of J-domain
      proteins including DNAJB6. The Reactome pathway correctly identifies DNAJB6 as stimulating
      HSP70 ATPase activity in the nucleoplasm. PMID:10954706 and UniProt both confirm this
      function. This is a core annotation.
    supported_by:
      - reference_id: PMID:10954706
        supporting_text: >-
          Mrj was immunoprecipitated not only with K18, but also with the stress-induced and constitutively
          expressed heat shock protein Hsp/c70.
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5251959
  review:
    summary: >-
      This TAS annotation from Reactome (R-HSA-5251959, HSP40s activate intrinsic ATPase activity
      of HSP70s in the cytosol) correctly identifies DNAJB6 as an activator of HSP70 ATPase
      activity in the cytosol. The Reactome pathway explicitly mentions DNAJB6 (as DNAJB6) among
      the HSP40s that dramatically increase HSP70 ATPase activity, citing Izawa et al. 2000
      (PMID:10954706). Duplicate of the nucleoplasm-specific annotation above but refers to the
      cytosolic context (isoform B).
    action: ACCEPT
    reason: >-
      Same core function as the nucleoplasm annotation above, but in the cytosolic compartment
      context. Both are valid as DNAJB6 isoforms function in both compartments. This is a
      core molecular function. The Reactome entry explicitly names DNAJB6 as an Hsp70 ATPase
      stimulator.
    supported_by:
      - reference_id: PMID:10954706
        supporting_text: >-
          Mrj was immunoprecipitated not only with K18, but also with the stress-induced and constitutively
          expressed heat shock protein Hsp/c70.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:21231916
  review:
    summary: >-
      PMID:21231916 (Hageman et al. 2011) systematically assessed Hsp70 and Hsp40 family members
      for chaperone activities and demonstrated functional interactions between DNAJB6 and HSP70s.
      The study showed that J-proteins including DNAJB6 stimulate Hsp70 ATPase activity, confirming
      the co-chaperone binding interaction. The IPI evidence from this study directly supports
      DNAJB6 binding to protein-folding chaperones (Hsp70s).
    action: ACCEPT
    reason: >-
      PMID:21231916 provides direct experimental evidence for DNAJB6 interacting with Hsp70
      family chaperones in functional assays. This is a core molecular function of J-domain
      proteins and is well supported by the experimental data in this publication.
    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. This was not related to client specificity itself, as the polyQ aggregation
          inhibitors often also suppressed heat-induced aggregation of luciferase.
- term:
    id: GO:0032880
    label: regulation of protein localization
  evidence_type: IMP
  original_reference_id: PMID:20889486
  review:
    summary: >-
      PMID:20889486 (Rose et al. 2011) demonstrated that DNAJB6 can rescue the relocation of
      misfolded Parkin (C289G mutant) to depolarized mitochondria, thereby restoring mitophagy.
      DNAJB6 co-expression rescued Parkin(C289G) redistribution to mitochondria in 16% of cells
      (comparable to HSJ1a ΔUIM mutant). This represents regulation of protein localization
      through chaperone-mediated refolding/stabilization of a misfolded client. However, this
      is a non-core function -- it reflects DNAJB6's general anti-aggregation chaperone activity
      applied to a specific client (misfolded Parkin) rather than a primary regulatory role in
      protein localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      The ability of DNAJB6 to rescue localization of misfolded Parkin to mitochondria (PMID:20889486)
      is a secondary consequence of its chaperone/anti-aggregation activity, not a primary role in
      regulating protein localization. DNAJB6 helps misfolded Parkin achieve its correct conformation,
      allowing it to relocate to mitochondria -- this is chaperone activity applied to a specific client
      rather than a core protein localization regulatory function.
    supported_by:
      - reference_id: PMID:20889486
        supporting_text: >-
          HSJ1a and DNAJB6 also restored mitophagy by promoting the relocation of Parkin(C289G) and the
          autophagy marker LC3 to depolarized mitochondria.
- term:
    id: GO:0090084
    label: negative regulation of inclusion body assembly
  evidence_type: IMP
  original_reference_id: PMID:20889486
  review:
    summary: >-
      PMID:20889486 (Rose et al. 2011) demonstrated that DNAJB6 suppresses Parkin(C289G) inclusion
      formation. HSJ1a and DNAJB6 both reduced aggregation of the misfolded Parkin RING1 domain
      mutant. This is consistent with DNAJB6's well-characterized anti-aggregation/holdase activity.
      The term GO:0090084 (negative regulation of inclusion body assembly) accurately captures
      this activity.
    action: ACCEPT
    reason: >-
      Suppression of inclusion body formation is a core function of DNAJB6. PMID:20889486
      demonstrated this specifically for misfolded Parkin, consistent with the broader
      anti-aggregation activity shown for polyglutamine proteins (PMID:11896048, PMID:20159555,
      PMID:21231916, PMID:22366786). This is a well-supported core annotation.
    supported_by:
      - reference_id: PMID:20889486
        supporting_text: >-
          Parkin(C289G) aggregation and inclusion formation were suppressed by the neuronal DnaJ/Hsp40
          chaperone HSJ1a(DNAJB2a). Importantly, HSJ1a and DNAJB6 also restored mitophagy by promoting
          the relocation of Parkin(C289G) and the autophagy marker LC3 to depolarized mitochondria.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  review:
    summary: >-
      PMID:19946888 is a membrane proteome study of NK cells that identified 1843 proteins from
      isolated membrane fractions. DNAJB6 was detected in this high-throughput proteomic analysis.
      However, DNAJB6 has no transmembrane domains and is not known to be a membrane protein. The
      detection likely reflects association with membrane-proximal complexes or contamination of
      membrane fractions with cytoplasmic proteins. The study itself notes that approximately 60%
      of identified proteins were not predicted membrane proteins but were "largely involved in
      cellular processes and molecular functions that could be predicted to be transiently associated
      with membranes."
    action: REMOVE
    reason: >-
      DNAJB6 is a soluble cytoplasmic/nuclear protein with no transmembrane domains. Detection
      in a membrane proteome study (PMID:19946888) likely reflects cytoplasmic contamination of
      membrane fractions or transient association. The study itself acknowledges that ~60% of
      identified proteins are not integral membrane proteins. No other evidence supports membrane
      localization for DNAJB6. UniProt lists cytoplasm and nucleus as subcellular locations,
      not membrane.
    supported_by:
      - reference_id: PMID:19946888
        supporting_text: >-
          approximately 40% of the identified proteins were predicted as plausible membrane proteins.
          The remaining species were largely involved in cellular processes and molecular functions
          that could be predicted to be transiently associated with membranes.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      PMID:21231916 (Hageman et al. 2011) demonstrated nuclear localization of DNAJB6 by
      direct assay (IDA). This is consistent with the well-established nuclear distribution
      of the DNAJB6a isoform and supported by multiple other studies.
    action: ACCEPT
    reason: >-
      Nuclear localization is well established for DNAJB6, particularly isoform A. The IDA
      evidence from PMID:21231916 adds direct experimental support to the IBA and other IDA
      annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      PMID:21231916 (Hageman et al. 2011) demonstrated cytosol localization of DNAJB6 by
      direct assay (IDA). This is consistent with the well-established cytosolic distribution
      of the DNAJB6b isoform.
    action: ACCEPT
    reason: >-
      Cytosol localization is well established for DNAJB6b. The IDA evidence from PMID:21231916
      provides direct experimental support.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      This IDA annotation from PMID:21231916 (Hageman et al., 2011) attributed unfolded protein binding to DNAJB6
      based on its ability to suppress aggregation of polyQ-expanded huntingtin and heat-denatured luciferase.
      However, the same study critically demonstrated that DNAJB6 could NOT stimulate refolding of heat-denatured
      luciferase, despite being a potent suppressor of aggregation. This dissociation between aggregation
      suppression and refolding indicates holdase-like rather than foldase activity. GO:0051082 is being obsoleted
      (go-ontology#30962). GO:0044183 (protein folding chaperone) is proposed as an interim replacement, but its
      definition ("Binding to a protein or a protein-containing complex to assist the protein folding process") is
      imprecise for DNAJB6 since the protein prevents aggregation rather than assists folding per se. A holdase
      activity term would be the ideal annotation but does not yet exist in GO.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted per go-ontology#30962. The IDA evidence from PMID:21231916 actually demonstrates
      that DNAJB6 is a holdase rather than a foldase: it suppresses polyQ aggregation and heat-induced luciferase
      aggregation, but cannot stimulate luciferase refolding. This is a key functional distinction. GO:0044183
      (protein folding chaperone) is proposed as the closest interim replacement, with the caveat that DNAJB6
      prevents aggregation (holdase activity) rather than assisting in productive folding. The polyQ aggregation
      inhibitors in this study "often also suppressed heat-induced aggregation of luciferase" confirming that
      DNAJB6 binds and stabilizes unfolded substrates, but channels them toward aggregation prevention rather than
      refolding.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    additional_reference_ids:
      - PMID:20159555
      - PMID:11896048
    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. This was not related to client specificity itself, as the polyQ aggregation
          inhibitors often also suppressed heat-induced aggregation of luciferase.
      - reference_id: PMID:11896048
        supporting_text: >-
          overexpressed MRJ effectively suppressed polyglutamine-dependent protein aggregation, caspase activity,
          and cellular toxicity
- term:
    id: GO:0090084
    label: negative regulation of inclusion body assembly
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      PMID:21231916 (Hageman et al. 2011) demonstrated that DNAJB6 is among the most potent
      suppressors of polyQ aggregation and inclusion body formation in the HSP70/HSP40 chaperone
      network. The study systematically tested all mammalian HSP70 and HSP40 members and found
      DNAJB6b to be a superior suppressor of polyQ inclusion body assembly. This is a core
      function of DNAJB6.
    action: ACCEPT
    reason: >-
      Suppression of inclusion body assembly is one of the most well-characterized functions
      of DNAJB6. PMID:21231916 provides direct experimental evidence (IDA) that DNAJB6 is a
      potent suppressor of polyQ aggregation. This is further supported by PMID:11896048,
      PMID:20159555, and PMID:22366786.
    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:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  review:
    summary: >-
      PMID:21630459 is a proteomic characterization of the human sperm nucleus that identified
      403 proteins. DNAJB6 was detected in isolated sperm nuclei by mass spectrometry. This HDA
      (high-throughput direct assay) provides additional evidence for nuclear localization, though
      in a specialized cell type (sperm). Nuclear localization of DNAJB6a is well established
      from other studies.
    action: ACCEPT
    reason: >-
      Detection of DNAJB6 in sperm nuclei by mass spectrometry (PMID:21630459) provides additional
      proteomic evidence for nuclear localization, consistent with the well-established nuclear
      distribution of DNAJB6a from multiple other studies.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5251955
  review:
    summary: >-
      This TAS annotation from Reactome (R-HSA-5251955, HSP40s activate intrinsic ATPase activity
      of HSP70s in the nucleoplasm) places DNAJB6 in the nucleoplasm as the site where it stimulates
      HSP70 ATPase activity. This is consistent with the nuclear localization of DNAJB6a and the
      HPA immunofluorescence data showing nucleoplasm localization.
    action: ACCEPT
    reason: >-
      Nucleoplasm localization is supported by the Reactome pathway placing DNAJB6 as an HSP70
      ATPase activator in the nucleoplasm, consistent with IDA evidence from HPA and the known
      nuclear distribution of DNAJB6a.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5251959
  review:
    summary: >-
      This TAS annotation from Reactome (R-HSA-5251959, HSP40s activate intrinsic ATPase activity
      of HSP70s in the cytosol) places DNAJB6 in the cytosol where it stimulates HSP70 ATPase
      activity. The Reactome entry explicitly names DNAJB6 among the HSP40s with this function.
      Consistent with the well-established cytosolic localization of DNAJB6b.
    action: ACCEPT
    reason: >-
      Cytosol localization is well supported by the Reactome pathway placing DNAJB6 as an HSP70
      ATPase activator in the cytosol, consistent with IDA evidence and the known cytosolic
      distribution of DNAJB6b.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22366786
  review:
    summary: >-
      PMID:22366786 (Sarparanta et al. 2012) demonstrated specific interactions of DNAJB6 with
      BAG3, HSPB8, and STUB1 (CHIP) -- members of the CASA (chaperone-assisted selective autophagy)
      complex -- by co-immunoprecipitation. These are functionally significant interactions linking
      DNAJB6 to Z-disk maintenance in muscle. However, GO:0005515 (protein binding) is uninformative.
      The interactions with CASA complex members are better described by GO:0051087 (protein-folding
      chaperone binding) for the chaperone interactions.
    action: MODIFY
    reason: >-
      PMID:22366786 demonstrates specific, functionally important interactions with BAG3, HSPB8,
      and STUB1 by co-immunoprecipitation. GO:0005515 (protein binding) is too general. The
      interactions with these CASA complex chaperone components are better captured by
      GO:0051087 (protein-folding chaperone binding), which is already annotated.
    proposed_replacement_terms:
      - id: GO:0051087
        label: protein-folding chaperone binding
    supported_by:
      - reference_id: PMID:22366786
        supporting_text: >-
          we show that DNAJB6 interacts with members of the CASA complex, including the myofibrillar
          myopathy-causing protein BAG3
- term:
    id: GO:0030018
    label: Z disc
  evidence_type: IDA
  original_reference_id: PMID:22366786
  review:
    summary: >-
      PMID:22366786 (Sarparanta et al. 2012) demonstrated by immunofluorescence microscopy
      that DNAJB6 localizes primarily to Z-disks in skeletal muscle. Electron microscopy of
      LGMD1D patient muscle revealed Z-disk myofibrillar disintegration, and DNAJB6 was found
      in protein accumulations at these sites. This localization is functionally relevant for
      the CASA complex-mediated Z-disk maintenance function.
    action: ACCEPT
    reason: >-
      Z disc localization is directly demonstrated by immunofluorescence in PMID:22366786 and
      is functionally significant for DNAJB6's role in muscle sarcomere maintenance via the
      CASA complex. LGMD1D mutations cause Z-disk disintegration, underscoring the importance
      of this localization. This is a core localization in skeletal muscle.
    supported_by:
      - reference_id: PMID:22366786
        supporting_text: >-
          Immunofluorescence (IF) microscopy showed DNAJB6 primarily in Z-disks in both control
          (not shown) and LGMD1D muscle samples (Fig. 1a). Electron microscopy (EM) of LGMD1D
          patient muscle revealed Z-disk myofibrillar disintegration (Fig. 1b).
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IDA
  original_reference_id: PMID:10954706
  review:
    summary: >-
      PMID:10954706 (Izawa et al. 2000) demonstrated by co-immunoprecipitation that DNAJB6 (Mrj)
      binds to Hsp/c70 (heat shock protein 70). The N-terminal J-domain region mediates this
      interaction. This is a core molecular function of all J-domain proteins. GO:0031072 (heat
      shock protein binding) is appropriate as it encompasses the Hsp70 binding activity and is
      consistent with the more specific GO:0030544 (Hsp70 protein binding).
    action: ACCEPT
    reason: >-
      Heat shock protein binding (specifically Hsp70) is the defining interaction for J-domain
      proteins. PMID:10954706 provides direct co-immunoprecipitation evidence. This is a core
      molecular function annotation.
    supported_by:
      - reference_id: PMID:10954706
        supporting_text: >-
          Mrj was immunoprecipitated not only with K18, but also with the stress-induced and constitutively
          expressed heat shock protein Hsp/c70. Mrj bound to K18 through its C terminus and interacted with
          Hsp/c70 via its N terminus, which contains the J domain.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  review:
    summary: >-
      This IDA annotation from curation of intracellular localizations of expressed fusion
      proteins in living cells confirms nuclear localization. Consistent with multiple other
      studies showing DNAJB6a nuclear localization.
    action: ACCEPT
    reason: >-
      Nuclear localization is thoroughly supported for DNAJB6a by multiple independent methods.
      This IDA from fusion protein localization adds further direct evidence.
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IDA
  original_reference_id: PMID:11896048
  review:
    summary: >-
      PMID:11896048 (Chuang et al. 2002) characterized DNAJB6 (MRJ) chaperone activity and
      showed it functions as a co-chaperone. The UniProt entry states "Has a stimulatory effect
      on the ATPase activity of HSP70 in a dose-dependent and time-dependent manner" citing
      PMID:10954706 and PMID:28233300. While PMID:11896048 focuses on the anti-aggregation
      activity rather than directly measuring ATPase stimulation, the co-chaperone function
      is integral to J-domain protein activity. The IDA from PMID:10954706 would be a more
      direct source for this annotation, but the co-chaperone function described in PMID:11896048
      is consistent.
    action: ACCEPT
    reason: >-
      ATPase activator activity toward Hsp70 is a core molecular function of DNAJB6 as a
      J-domain co-chaperone. UniProt confirms dose-dependent and time-dependent stimulation
      of HSP70 ATPase activity. This is a core annotation.
    supported_by:
      - reference_id: PMID:11896048
        supporting_text: >-
          we describe the isolation of a DnaJ-like protein MRJ and the characterization of its
          chaperone activity
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:10954706
  review:
    summary: >-
      PMID:10954706 (Izawa et al. 2000) showed nuclear localization of DNAJB6 (Mrj) by
      immunostaining. The UniProt subcellular location annotation cites this study as evidence
      for nuclear localization. This is consistent with the predominantly nuclear distribution
      of DNAJB6a.
    action: ACCEPT
    reason: >-
      Nuclear localization is directly demonstrated by immunostaining in PMID:10954706 and
      confirmed by UniProt annotation. This is a core localization for DNAJB6a.
    supported_by:
      - reference_id: PMID:10954706
        supporting_text: >-
          Immunostaining with anti-Mrj antibody showed that Mrj colocalized with K8/18 filaments in HeLa cells.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:11896048
  review:
    summary: >-
      PMID:11896048 (Chuang et al. 2002) demonstrated DNAJB6 chaperone activity in suppressing
      polyglutamine aggregation. As discussed above for the IBA annotation of this same term,
      DNAJB6 specifically acts as a holdase (preventing aggregation) rather than a foldase (refolding
      denatured proteins). GO:0006457 (protein folding) as a biological process encompasses the
      broader protein quality control pathway. The IDA evidence from PMID:11896048 demonstrates
      chaperone activity that contributes to the protein folding/quality control pathway, even
      though the specific mechanism is anti-aggregation rather than productive refolding.
    action: ACCEPT
    reason: >-
      GO:0006457 (protein folding) as a BP is broadly appropriate for DNAJB6's participation
      in the Hsp70-dependent protein quality control pathway. PMID:11896048 provides direct
      evidence of chaperone activity. While DNAJB6 specifically prevents aggregation rather
      than promoting refolding, the protein folding BP encompass quality control.
    supported_by:
      - reference_id: PMID:11896048
        supporting_text: >-
          overexpressed MRJ effectively suppressed polyglutamine-dependent protein aggregation,
          caspase activity, and cellular toxicity
- term:
    id: GO:0045109
    label: intermediate filament organization
  evidence_type: IDA
  original_reference_id: PMID:10954706
  review:
    summary: >-
      PMID:10954706 (Izawa et al. 2000) demonstrated that DNAJB6 (Mrj) plays an essential role
      in K8/18 intermediate filament organization. Microinjection of anti-Mrj antibody resulted
      in disorganization of K8/18 filaments without affecting actin filaments or microtubules.
      DNAJB6 bound to K18 through its C-terminus and functioned as a K18-specific co-chaperone
      with Hsp/c70. This is a well-supported core function directly demonstrated by loss-of-function
      (antibody microinjection) experiments.
    action: ACCEPT
    reason: >-
      Intermediate filament organization is a directly demonstrated function of DNAJB6, supported
      by both gain-of-function (co-immunoprecipitation with K18, colocalization with K8/18 filaments)
      and loss-of-function (anti-Mrj antibody microinjection causing filament disorganization)
      experiments in PMID:10954706. This is a core biological process function. The UniProt entry
      also states DNAJB6 "Plays an indispensable role in the organization of KRT8/KRT18 filaments."
    supported_by:
      - reference_id: PMID:10954706
        supporting_text: >-
          Microinjection of anti-Mrj antibody resulted in the disorganization of K8/18 filaments,
          without effects on the organization of actin filaments and microtubules. Taken together,
          these results suggest that Mrj may play an important role in the regulation of K8/18
          filament organization as a K18-specific co-chaperone working together with Hsp/c70.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:10954706
  review:
    summary: >-
      PMID:10954706 (Izawa et al. 2000) demonstrated perinuclear localization of DNAJB6 (Mrj)
      by immunostaining. The UniProt subcellular location explicitly states "Cytoplasm, perinuclear
      region" with ECO:0000269|PubMed:10954706 evidence. This is a well-supported localization.
    action: ACCEPT
    reason: >-
      Perinuclear localization is directly demonstrated by immunostaining in PMID:10954706 and
      annotated in UniProt subcellular location. This is a core localization.
    supported_by:
      - reference_id: PMID:10954706
        supporting_text: >-
          Immunostaining with anti-Mrj antibody showed that Mrj colocalized with K8/18 filaments in HeLa cells.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IDA
  original_reference_id: PMID:11896048
  review:
    summary: >-
      PMID:11896048 (Chuang et al. 2002) characterized DNAJB6 (MRJ) as a co-chaperone that
      interacts with the Hsp70 chaperone network. As a J-domain protein, DNAJB6 binds and
      stimulates Hsp70 family chaperones. The IDA evidence supports the protein-folding chaperone
      binding annotation, consistent with the established co-chaperone function.
    action: ACCEPT
    reason: >-
      Protein-folding chaperone binding (Hsp70 interaction) is a core molecular function
      of DNAJB6 as a J-domain co-chaperone. PMID:11896048 provides evidence for this
      co-chaperone function, and it is consistent with the more detailed binding data
      from PMID:10954706.
    supported_by:
      - reference_id: PMID:11896048
        supporting_text: >-
          we describe the isolation of a DnaJ-like protein MRJ and the characterization of its
          chaperone activity
core_functions:
  - molecular_function:
      id: GO:0044183
      label: protein folding chaperone
    description: >-
      DNAJB6 is a class B J-domain co-chaperone that functions as a potent holdase rather
      than a foldase. It prevents aggregation of polyglutamine-expanded proteins, tau, and
      other aggregation-prone substrates, but cannot stimulate refolding of denatured
      proteins. DNAJB6 functions within the HSP70 chaperone network, requiring its J-domain
      for anti-aggregation activity. The DNAJB6b (short, cytosolic) isoform is particularly
      important for suppression of protein aggregation, while DNAJB6a (long) is
      predominantly nuclear. Mutations in DNAJB6 cause limb-girdle muscular dystrophy
      type D1 (LGMDD1).
    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:11896048
        supporting_text: >-
          overexpressed MRJ effectively suppressed polyglutamine-dependent protein aggregation, caspase
          activity, and cellular toxicity
    directly_involved_in:
      - id: GO:0090084
        label: negative regulation of inclusion body assembly
      - id: GO:0006457
        label: protein folding
    locations:
      - id: GO:0005829
        label: cytosol
      - id: GO:0005654
        label: nucleoplasm
      - id: GO:0030018
        label: Z disc
      - id: GO:0048471
        label: perinuclear region of cytoplasm
  - molecular_function:
      id: GO:0001671
      label: ATPase activator activity
    description: >-
      DNAJB6 stimulates the intrinsic ATPase activity of HSP70/Hsc70 via its J-domain
      in both the cytosol and nucleoplasm. This is the defining co-chaperone function of
      J-domain proteins, confirmed by co-immunoprecipitation with Hsp/c70 and Reactome
      pathway annotations.
    supported_by:
      - reference_id: PMID:10954706
        supporting_text: >-
          Mrj was immunoprecipitated not only with K18, but also with the stress-induced and constitutively
          expressed heat shock protein Hsp/c70.
      - reference_id: PMID:11896048
        supporting_text: >-
          we describe the isolation of a DnaJ-like protein MRJ and the characterization of its
          chaperone activity
    directly_involved_in:
      - id: GO:0006457
        label: protein folding
    locations:
      - id: GO:0005829
        label: cytosol
      - id: GO:0005654
        label: nucleoplasm
  - molecular_function:
      id: GO:0030544
      label: Hsp70 protein binding
    description: >-
      DNAJB6 binds to keratin 18 (K18) via its C-terminus and to Hsp70/Hsc70 via its
      N-terminal J-domain, functioning as a K18-specific co-chaperone that regulates
      intermediate filament organization. Anti-Mrj antibody microinjection causes K8/18
      filament disorganization, establishing DNAJB6 as essential for keratin filament
      maintenance.
    supported_by:
      - reference_id: PMID:10954706
        supporting_text: >-
          Microinjection of anti-Mrj antibody resulted in the disorganization of K8/18 filaments,
          without effects on the organization of actin filaments and microtubules. Taken together,
          these results suggest that Mrj may play an important role in the regulation of K8/18
          filament organization as a K18-specific co-chaperone working together with Hsp/c70.
    directly_involved_in:
      - id: GO:0045109
        label: intermediate filament organization
    locations:
      - id: GO:0005737
        label: cytoplasm
      - id: GO:0048471
        label: perinuclear region of cytoplasm
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:0000054
  title: Gene Ontology annotation based on curation of intracellular localizations
    of expressed fusion proteins in living cells
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10954706
  title: Identification of Mrj, a DnaJ/Hsp40 family protein, as a keratin 8/18 filament
    regulatory protein.
  findings: []
- id: PMID:11896048
  title: Characterization of a brain-enriched chaperone, MRJ, that inhibits Huntingtin
    aggregation and toxicity independently.
  findings: []
- id: PMID:16919237
  title: Breast cancer metastasis suppressor 1 (BRMS1) is stabilized by the Hsp90
    chaperone.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20159555
  title: A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic
    protein aggregation.
  findings: []
- id: PMID:20889486
  title: Molecular chaperone-mediated rescue of mitophagy by a Parkin RING1 domain
    mutant.
  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:22366786
  title: Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6
    cause limb-girdle muscular dystrophy.
  findings: []
- id: PMID:23414517
  title: 'A human skeletal muscle interactome centered on proteins involved in muscular
    dystrophies: LGMD interactome.'
  findings: []
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of
    cellular protein homeostasis pathways.
  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:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: Reactome:R-HSA-3371453
  title: Regulation of HSF1-mediated heat shock response
  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: []