id: Q8NHS0
gene_symbol: DNAJB8
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  DNAJB8 is a class B J-domain protein (Hsp40/DNAJ family, subfamily B) that
  functions as a potent holdase chaperone suppressing polyglutamine and other
  aggregation-prone protein aggregation. Its domain architecture comprises an
  N-terminal J-domain (JD), a G/F-rich region, an S/T-rich region containing
  the key 147-AFSSFN-152 steric-zipper oligomerization motif, and a C-terminal
  domain (CTD). A key regulatory mechanism is an intramolecular JD-CTD
  interaction that can sequester the JD surface and control Hsp70 recruitment
  as a reversible switch (DOI:10.1038/s41467-021-21147-x). Unlike canonical
  DNAJ co-chaperones that assist Hsp70-mediated protein refolding, DNAJB8 acts
  primarily as a holdase, with anti-aggregation activity largely independent of
  the J-domain residing in the C-terminal serine-rich (SSF-SST) region and
  C-terminal tail (PMID:20159555). DNAJB8 self-assembles into oligomeric puncta
  via the AFSSFN steric-zipper motif (resolved at 0.75 angstrom by MicroED,
  class 6 steric zipper), but engineered monomeric variants retain substrate
  binding and anti-aggregation function, demonstrating that oligomerization is
  mechanistically separable from chaperone activity (DOI:10.1016/j.str.2024.02.015).
  DNAJB8 uses distinct substrate-binding modes: a serine-rich stretch for
  fibrillar/amyloid aggregation suppression and a separate CTD TTK-LKS motif
  for amorphous inclusion suppression via Hsp70-dependent proteasomal degradation
  (DOI:10.1242/jcs.255596). DNAJB8 is also a cancer-testis antigen preferentially
  expressed in renal and colorectal cancer stem-like cells, controlling
  tumor-initiating capacity (DOI:10.1158/0008-5472.CAN-11-3062), and promotes
  oxaliplatin chemoresistance in colon cancer via TP53 stabilization leading to
  MDR1/P-gp upregulation (DOI:10.1038/s41419-022-04599-x). DNAJB8 is enriched
  in testis but expressed in multiple tissues, and localizes to both cytosol and
  nucleus.
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for cytoplasm localization is well supported. DNAJB8 is a
      cytoplasmic J-domain co-chaperone. Hageman et al. (PMID:21231916) showed by
      direct assay that DNAJB8 localizes to the cytosol (IDA for GO:0005829,
      cytosol). The IBA phylogenetic inference is consistent with experimental
      data for both DNAJB8 and its close paralogue DNAJB6, which is also
      cytoplasmic. Note that cytoplasm (GO:0005737) is broader than cytosol
      (GO:0005829) but the IBA annotation at this level is appropriate given the
      phylogenetic evidence base.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is confirmed by IDA evidence from PMID:21231916
      for the more specific term cytosol (GO:0005829), and is consistent with the
      function of DNAJB8 as a cytoplasmic holdase chaperone that suppresses polyQ
      aggregation (PMID:20159555). The IBA inference is phylogenetically sound
      given conservation across DNAJB6/DNAJB8 orthologues.
    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:20159555
      supporting_text: >-
        members of a subclass of the DNAJB family (particularly DNAJB6b and
        DNAJB8) are superior suppressors of aggregation and toxicity of
        disease-associated polyglutamine proteins.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for protein folding (GO:0006457) is broadly acceptable as
      DNAJB8 is a J-domain co-chaperone involved in proteostasis. However,
      DNAJB8 acts primarily as a holdase that suppresses aggregation of
      polyQ-expanded proteins rather than promoting productive protein folding
      (PMID:21231916, PMID:20159555). Hageman et al. (PMID:21231916) showed that
      chaperones suppressing polyQ aggregation (like DNAJB8) could not stimulate
      luciferase refolding, distinguishing holdase from foldase activities.
      The term protein folding is therefore somewhat imprecise for DNAJB8, but
      the broader proteostasis role is real. As an IBA annotation it represents a
      reasonable phylogenetic inference at an appropriate level of specificity.
    action: ACCEPT
    reason: >-
      Although DNAJB8 is functionally a holdase rather than a canonical foldase,
      it participates in the broader protein folding quality control network as a
      J-domain co-chaperone. The IBA phylogenetic inference is sound for the DNAJB
      subfamily. The qualifier in GOA is 'involved_in' which is appropriate for a
      chaperone that participates in protein folding pathways even if its specific
      role is aggregation suppression rather than productive folding. Experimental
      support comes from PMID:23612975 (IDA for the same term) and 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.
    - reference_id: PMID:23612975
      supporting_text: >-
        we expressed polyQ peptides in cells and show that their intracellular
        aggregation is prevented by DNAJB6 and DNAJB8, members of the DNAJ
        (Hsp40) chaperone family.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for nuclear localization is well supported. DNAJB8 has been
      shown to localize to the nucleus by IDA (PMID:21231916) and HDA
      (PMID:21630459, sperm nuclear proteomics). The IBA phylogenetic inference
      is consistent with experimental data for DNAJB8 itself and with the known
      nuclear localization of its close paralogue DNAJB6a.
    action: ACCEPT
    reason: >-
      Nuclear localization of DNAJB8 is confirmed by multiple independent lines
      of evidence: IDA from PMID:21231916 (direct assay showing nuclear
      localization) and HDA from PMID:21630459 (identified in human sperm nuclear
      proteome). The IBA phylogenetic inference is consistent with these
      experimental observations and with the dual cytosol/nucleus localization
      pattern of the DNAJB6/B8 subfamily.
    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:21630459
      supporting_text: >-
        403 different proteins have been identified from the isolated sperm
        nuclei.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for protein-folding chaperone binding (GO:0051087) is well
      supported. DNAJB8 is a J-domain co-chaperone that physically interacts with
      Hsp70 family members (HSPA1A/P0DMV8, HSPA1B/P0DMV9, HSPA6/P17066) as
      shown by IPI evidence from PMID:21231916. The J-domain of DNAJB8 stimulates
      Hsp70 ATPase activity, which is the canonical mechanism of J-domain protein
      function. The IBA phylogenetic inference is consistent with this being a
      core function of J-domain proteins across the DNAJB subfamily.
    action: ACCEPT
    reason: >-
      Chaperone binding is a core molecular function of J-domain proteins.
      DNAJB8 contains a canonical J-domain (residues 3-69, UniProt) that mediates
      interaction with Hsp70 chaperones. IPI evidence from PMID:21231916 directly
      demonstrates physical interaction with multiple Hsp70 family members. The
      IBA phylogenetic inference is phylogenetically sound and at the right level
      of specificity.
    supported_by:
    - reference_id: PMID:20159555
      supporting_text: >-
        The antiaggregation activity is largely independent of the N-terminal
        Hsp70-interacting J-domain. Rather, a C-terminal serine-rich (SSF-SST)
        region and the C-terminal tail are essential.
    - reference_id: PMID:21231916
      supporting_text: >-
        Overexpressed chaperones that suppressed polyQ aggregation were found not
        to be able to stimulate luciferase refolding.
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for protein folding chaperone (GO:0044183) is well supported
      and represents a core molecular function of DNAJB8. This term describes the
      activity of binding to a protein to assist the protein folding process,
      which is the canonical function of J-domain co-chaperones. DNAJB8
      specifically acts as a holdase chaperone that binds polyQ-expanded proteins
      and other aggregation-prone substrates to prevent their aggregation
      (PMID:20159555, PMID:23612975). IDA evidence for this same term exists from
      PMID:23612975. The IBA phylogenetic inference is sound and at the right
      level of specificity for the DNAJB subfamily.
    action: ACCEPT
    reason: >-
      GO:0044183 (protein folding chaperone) is the best available GO molecular
      function term for DNAJB8's holdase/anti-aggregation chaperone activity.
      DNAJB8 binds aggregation-prone substrates to prevent their misfolding and
      aggregation, which falls within the scope of this term. IDA evidence from
      PMID:23612975 independently supports this annotation. The IBA phylogenetic
      inference is consistent with the conserved chaperone function across the
      DNAJB6/B8 clade.
    supported_by:
    - reference_id: PMID:23612975
      supporting_text: >-
        we conclude that the mechanism of DNAJB6 and DNAJB8 is suppression of
        polyQ protein aggregation by directly binding the polyQ tract.
    - reference_id: PMID:20159555
      supporting_text: >-
        members of a subclass of the DNAJB family (particularly DNAJB6b and
        DNAJB8) are superior suppressors of aggregation and toxicity of
        disease-associated polyglutamine proteins.
- 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).
      While DNAJB8 does bind unfolded/aggregation-prone substrates, this term
      does not accurately capture its functional activity. DNAJB8 is a holdase
      chaperone that binds polyQ-expanded proteins and other aggregation-prone
      substrates to prevent their aggregation, largely independently of Hsp70
      (PMID:20159555). The best available replacement term is GO:0044183 (protein
      folding chaperone), which is already annotated via IBA and IDA evidence for
      this gene. Note that DNAJB8 is functionally a holdase rather than a foldase,
      but no dedicated holdase term currently exists in GO.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. DNAJB8 does bind unfolded/misfolded proteins,
      but this binding is in the context of its holdase chaperone activity --
      it prevents aggregation of polyQ substrates rather than merely binding
      unfolded proteins passively. The recommended interim replacement is
      GO:0044183 (protein folding chaperone), which better captures the functional
      activity, though it is imprecise for a holdase. DNAJB8 already has
      GO:0044183 annotations (IBA and IDA), so this modification aligns the
      annotation set. Hageman et al. (PMID:20159555) showed that the
      anti-aggregation activity of DNAJB8 is largely independent of the J-domain
      and resides in the C-terminal serine-rich region, demonstrating direct
      substrate binding in a holdase capacity. Gillis et al. (PMID:23612975)
      confirmed that DNAJB6 and DNAJB8 inhibit polyQ peptide aggregation
      directly by binding the polyQ tract.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:20159555
    - PMID:23612975
    supported_by:
    - reference_id: PMID:20159555
      supporting_text: >-
        members of a subclass of the DNAJB family (particularly DNAJB6b and
        DNAJB8) are superior suppressors of aggregation and toxicity of
        disease-associated polyglutamine proteins. The antiaggregation activity
        is largely independent of the N-terminal Hsp70-interacting J-domain.
        Rather, a C-terminal serine-rich (SSF-SST) region and the C-terminal
        tail are essential. The SSF-SST region is involved in substrate binding,
        formation of polydisperse oligomeric complexes, and interaction with
        histone deacetylases (HDAC4, HDAC6, SIRT2).
    - reference_id: PMID:23612975
      supporting_text: >-
        we conclude that the mechanism of DNAJB6 and DNAJB8 is suppression of
        polyQ protein aggregation by directly binding the polyQ tract.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation for cytoplasm localization from ARBA machine learning
      models. This is consistent with the IBA annotation for cytoplasm and the
      IDA annotation for the more specific term cytosol (GO:0005829) from
      PMID:21231916. The IEA annotation is broader than the experimentally
      determined cytosol localization but is not incorrect.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is confirmed by IDA evidence for cytosol
      (PMID:21231916) and by IBA phylogenetic inference. The IEA annotation is
      redundant with but consistent with higher-quality evidence. Acceptable as a
      broader computational annotation that aligns with experimental data.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        Overexpressed chaperones that suppressed polyQ aggregation were found not
        to be able to stimulate luciferase refolding.
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for Hsp70 protein binding (GO:0030544) inferred from the
      InterPro domain IPR043183 (DNJB2/6-like). DNAJB8 contains a canonical
      J-domain (residues 3-69) that mediates physical interaction with Hsp70
      family chaperones. Hageman et al. (PMID:21231916) demonstrated by IPI that
      DNAJB8 physically interacts with HSPA1A (P0DMV8), HSPA1B (P0DMV9), and
      HSPA6 (P17066), all Hsp70 family members. While the IPI annotations are
      curated under the broader GO:0051087 (protein-folding chaperone binding),
      Hsp70 binding is a well-established core function of J-domain proteins.
      This IEA annotation is more specific than GO:0051087 regarding the binding
      partner identity and is well supported.
    action: ACCEPT
    reason: >-
      Hsp70 binding is the canonical function of J-domain proteins. DNAJB8 has a
      well-characterized J-domain (UniProt domain annotation, residues 3-69) and
      IPI evidence from PMID:21231916 confirms physical interaction with three
      Hsp70 family members. The InterPro-based IEA inference from IPR043183 is
      correct and specific. Hageman et al. (PMID:20159555) further showed that
      while the antiaggregation activity of DNAJB8 is largely J-domain
      independent, the J-domain still mediates Hsp70 interaction.
    supported_by:
    - reference_id: PMID:20159555
      supporting_text: >-
        The antiaggregation activity is largely independent of the N-terminal
        Hsp70-interacting J-domain. Rather, a C-terminal serine-rich (SSF-SST)
        region and the C-terminal tail are essential.
    - reference_id: PMID:21231916
      supporting_text: >-
        Overexpressed chaperones that suppressed polyQ aggregation were found not
        to be able to stimulate luciferase refolding.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962).
      This IEA annotation was inferred from the InterPro domain IPR043183
      (DNJB2/6-like), which is shared across DNAJB2, DNAJB6, and DNAJB8. While
      these proteins do interact with unfolded/misfolded substrates, the term
      fails to capture the functional nature of the interaction. DNAJB8
      specifically acts as a holdase chaperone that suppresses aggregation of
      polyQ-expanded proteins by directly binding the polyQ tract (PMID:20159555,
      PMID:23612975). The best interim replacement is GO:0044183 (protein folding
      chaperone), noting that DNAJB8 is a holdase rather than a foldase and no
      dedicated holdase GO term currently exists.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. The InterPro-based IEA mapping from
      IPR043183 correctly identified that DNAJB8 interacts with unfolded
      substrates, but GO:0044183 (protein folding chaperone) is the recommended
      replacement that better captures the functional chaperone activity. DNAJB8
      already has GO:0044183 annotations from both IBA and IDA evidence. Caveat:
      DNAJB8 functions as a holdase rather than a foldase -- it suppresses
      aggregation rather than promoting productive folding -- but GO currently
      lacks a dedicated holdase term.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:20159555
    - PMID:23612975
    supported_by:
    - reference_id: PMID:20159555
      supporting_text: >-
        members of a subclass of the DNAJB family (particularly DNAJB6b and
        DNAJB8) are superior suppressors of aggregation and toxicity of
        disease-associated polyglutamine proteins. The antiaggregation activity
        is largely independent of the N-terminal Hsp70-interacting J-domain.
    - reference_id: PMID:23612975
      supporting_text: >-
        we conclude that the mechanism of DNAJB6 and DNAJB8 is suppression of
        polyQ protein aggregation by directly binding the polyQ tract.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation for protein-folding chaperone binding from ARBA machine
      learning models. This is consistent with the IBA annotation and the IPI
      evidence from PMID:21231916 showing DNAJB8 physically interacts with
      Hsp70 chaperones (HSPA1A, HSPA1B, HSPA6). The computational inference is
      correct and redundant with higher-quality evidence.
    action: ACCEPT
    reason: >-
      Protein-folding chaperone binding is well established for DNAJB8 through
      IPI evidence (PMID:21231916) and IBA phylogenetic inference. The IEA
      annotation is redundant with but consistent with these higher-quality
      annotations.
    supported_by:
    - reference_id: PMID:21231916
      supporting_text: >-
        Overexpressed chaperones that suppressed polyQ aggregation were found not
        to be able to stimulate luciferase refolding.
- term:
    id: GO:0090084
    label: negative regulation of inclusion body assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation for negative regulation of inclusion body assembly from ARBA
      machine learning models. DNAJB8 is a potent suppressor of polyQ protein
      aggregation and inclusion body formation (PMID:20159555, PMID:23612975).
      Hageman et al. (PMID:20159555) demonstrated that DNAJB8 suppresses
      aggregation and toxicity of disease-associated polyglutamine proteins.
      Gillis et al. (PMID:23612975) showed that DNAJB8 prevents intracellular
      aggregation of polyQ peptides. This is a core function of DNAJB8 and the
      IEA annotation is well supported by IDA evidence from PMID:21231916 for
      the same term.
    action: ACCEPT
    reason: >-
      Negative regulation of inclusion body assembly is a core function of
      DNAJB8, supported by IDA evidence from PMID:21231916 and extensive
      experimental literature (PMID:20159555, PMID:23612975). The IEA annotation
      is redundant with but consistent with the higher-quality IDA annotation.
    supported_by:
    - reference_id: PMID:20159555
      supporting_text: >-
        members of a subclass of the DNAJB family (particularly DNAJB6b and
        DNAJB8) are superior suppressors of aggregation and toxicity of
        disease-associated polyglutamine proteins.
    - reference_id: PMID:23612975
      supporting_text: >-
        we expressed polyQ peptides in cells and show that their intracellular
        aggregation is prevented by DNAJB6 and DNAJB8, members of the DNAJ
        (Hsp40) chaperone family.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IPI annotation for protein-folding chaperone binding based on physical
      interaction evidence from Hageman et al. (PMID:21231916). The GOA records
      three separate IPI entries for this annotation, each with a different Hsp70
      interacting partner: HSPA1A (UniProtKB:P0DMV8), HSPA1B (UniProtKB:P0DMV9),
      and HSPA6 (UniProtKB:P17066). This study systematically tested the
      chaperone activities of HSP70 and DNAJ family members and demonstrated
      physical interactions between DNAJB8 and these Hsp70 proteins. DNAJB8
      contains a canonical J-domain (residues 3-69) that mediates Hsp70
      interaction. This is a core molecular function of J-domain co-chaperones.
    action: ACCEPT
    reason: >-
      Physical interaction between DNAJB8 and Hsp70 chaperones is directly
      demonstrated by co-immunoprecipitation or equivalent assays in Hageman et
      al. (PMID:21231916). The J-domain of DNAJB8 is the canonical Hsp70
      interaction module. This annotation is well supported and represents a core
      function. The term protein-folding chaperone binding (GO:0051087) is
      appropriate as it captures the interaction with Hsp70 chaperones, which are
      protein-folding chaperones.
    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:20159555
      supporting_text: >-
        The antiaggregation activity is largely independent of the N-terminal
        Hsp70-interacting J-domain. Rather, a C-terminal serine-rich (SSF-SST)
        region and the C-terminal tail are essential.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IDA annotation for nuclear localization from Hageman et al.
      (PMID:21231916). This study examined the subcellular localization of
      overexpressed DNAJB8 using fluorescence microscopy or similar direct
      assays, demonstrating both nuclear and cytosolic localization. Nuclear
      localization is independently supported by the HDA annotation from
      PMID:21630459 (sperm nuclear proteomics) and the IBA phylogenetic
      inference. The close paralogue DNAJB6 also shows nuclear localization,
      with the DNAJB6a isoform being predominantly nuclear. DNAJB8 localizes
      to both cytosol and nucleus, consistent with the description in UniProt.
    action: ACCEPT
    reason: >-
      Nuclear localization is directly demonstrated by Hageman et al.
      (PMID:21231916) and independently confirmed by sperm nuclear proteomics
      (PMID:21630459). The dual cytosol/nucleus localization is consistent with
      the known biology of the DNAJB6/B8 subfamily and with a potential role
      in nuclear proteostasis.
    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:21630459
      supporting_text: >-
        403 different proteins have been identified from the isolated sperm
        nuclei.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IDA annotation for cytosol localization from Hageman et al.
      (PMID:21231916). DNAJB8 was shown by direct assay to localize to the
      cytosol. This is consistent with its function as a cytoplasmic holdase
      chaperone that suppresses polyQ protein aggregation (PMID:20159555,
      PMID:23612975). The cytosol is the primary site where DNAJB8 encounters
      and binds aggregation-prone substrates. This is also consistent with the
      IBA annotation for the broader term cytoplasm (GO:0005737).
    action: ACCEPT
    reason: >-
      Cytosolic localization is directly demonstrated by Hageman et al.
      (PMID:21231916) and is consistent with the primary function of DNAJB8 as
      a cytoplasmic holdase chaperone. The cytosol is where polyQ-expanded
      proteins aggregate and where DNAJB8 exerts its anti-aggregation activity.
    supported_by:
    - reference_id: PMID:20159555
      supporting_text: >-
        members of a subclass of the DNAJB family (particularly DNAJB6b and
        DNAJB8) are superior suppressors of aggregation and toxicity of
        disease-associated polyglutamine proteins.
    - reference_id: PMID:21231916
      supporting_text: >-
        Overexpressed chaperones that suppressed polyQ aggregation were found not
        to be able to stimulate luciferase refolding.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962).
      This IDA annotation cites PMID:21231916 (Hageman et al. 2011), which
      demonstrated that different HSP70/DNAJ family members have distinct
      chaperone-like activities. Chaperones that suppressed polyQ aggregation
      (holdase activity) were found not to stimulate luciferase refolding
      (foldase activity), and vice versa (PMID:21231916). DNAJB8 falls in
      the holdase category. The earlier study by the same group (PMID:20159555,
      Hageman et al. 2010) specifically showed DNAJB8 is a superior suppressor
      of polyQ aggregation with activity largely independent of its J-domain.
      Gillis et al. (PMID:23612975) further confirmed that DNAJB8 suppresses
      polyQ protein aggregation by directly binding the polyQ tract. The best
      interim replacement is GO:0044183 (protein folding chaperone), with the
      caveat that DNAJB8 is a holdase, not a foldase, and no dedicated holdase
      GO term currently exists.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. The experimental evidence from Hageman et al.
      (PMID:21231916) demonstrated that DNAJB8 has chaperone-like holdase activity
      rather than mere unfolded protein binding. The study showed that chaperones
      suppressing polyQ aggregation could not stimulate luciferase refolding,
      establishing a functional distinction between holdase and foldase activities.
      GO:0044183 (protein folding chaperone) is the best available replacement
      term, though it is imprecise for a holdase. DNAJB8 already has GO:0044183
      annotations from IBA and IDA (PMID:23612975) evidence. The IDA evidence
      supporting the original GO:0051082 annotation is consistent with chaperone
      activity and should be retained under the replacement term.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:20159555
    - PMID:23612975
    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:20159555
      supporting_text: >-
        members of a subclass of the DNAJB family (particularly DNAJB6b and
        DNAJB8) are superior suppressors of aggregation and toxicity of
        disease-associated polyglutamine proteins. The antiaggregation activity
        is largely independent of the N-terminal Hsp70-interacting J-domain.
        Rather, a C-terminal serine-rich (SSF-SST) region and the C-terminal
        tail are essential.
    - reference_id: PMID:23612975
      supporting_text: >-
        we expressed polyQ peptides in cells and show that their intracellular
        aggregation is prevented by DNAJB6 and DNAJB8, members of the DNAJ
        (Hsp40) chaperone family. In contrast, HSPA/Hsp70 and DNAJB1, also
        members of the DNAJ chaperone family, did not prevent peptide-initiated
        aggregation.
- term:
    id: GO:0090084
    label: negative regulation of inclusion body assembly
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      IDA annotation for negative regulation of inclusion body assembly from
      Hageman et al. (PMID:21231916). This study demonstrated that DNAJB8
      suppresses polyQ aggregation, which directly manifests as prevention of
      inclusion body formation. The earlier study by the same group
      (PMID:20159555) showed DNAJB8 is a superior suppressor of aggregation
      and toxicity of disease-associated polyglutamine proteins, with the
      antiaggregation activity residing in the C-terminal serine-rich region.
      Gillis et al. (PMID:23612975) independently confirmed that DNAJB8
      prevents intracellular aggregation of polyQ peptides by directly binding
      the polyQ tract. This is a core function of DNAJB8 and the annotation is
      well supported by direct experimental evidence.
    action: ACCEPT
    reason: >-
      Negative regulation of inclusion body assembly is directly demonstrated
      by multiple studies. Hageman et al. (PMID:21231916) showed DNAJB8
      suppresses polyQ aggregation in cellular assays. The same group
      (PMID:20159555) established the mechanism involving C-terminal
      substrate binding and HDAC interactions. Gillis et al. (PMID:23612975)
      confirmed DNAJB8 prevents intracellular polyQ peptide aggregation. This
      is arguably the most distinctive and potent function of DNAJB8.
    additional_reference_ids:
    - PMID:20159555
    - PMID:23612975
    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:20159555
      supporting_text: >-
        members of a subclass of the DNAJB family (particularly DNAJB6b and
        DNAJB8) are superior suppressors of aggregation and toxicity of
        disease-associated polyglutamine proteins. The antiaggregation activity
        is largely independent of the N-terminal Hsp70-interacting J-domain.
    - reference_id: PMID:23612975
      supporting_text: >-
        we expressed polyQ peptides in cells and show that their intracellular
        aggregation is prevented by DNAJB6 and DNAJB8, members of the DNAJ
        (Hsp40) chaperone family. In contrast, HSPA/Hsp70 and DNAJB1, also
        members of the DNAJ chaperone family, did not prevent peptide-initiated
        aggregation.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  review:
    summary: >-
      HDA annotation for nuclear localization from de Mateo et al.
      (PMID:21630459), a proteomic characterization of the human sperm nucleus.
      DNAJB8 was identified among 403 proteins in isolated human sperm nuclei by
      LC-MS/MS. DNAJB8 is enriched in testis (HPA: tissue enriched in testis;
      Bgee: expressed in sperm), so its detection in the sperm nuclear proteome
      is biologically plausible. However, this is a high-throughput proteomics
      study and the nuclear detection could reflect a genuine nuclear pool or
      could be a consequence of the protein being highly abundant in testis.
      The nuclear localization is independently supported by IDA evidence from
      PMID:21231916. DNAJB8 is known to localize to both cytosol and nucleus.
    action: ACCEPT
    reason: >-
      The HDA evidence from sperm nuclear proteomics is consistent with the IDA
      evidence for nuclear localization from PMID:21231916 and with the IBA
      phylogenetic inference. While high-throughput proteomics can have
      contaminants, the fact that DNAJB8 is testis-enriched and independently
      shown to be nuclear by direct assay supports the biological relevance of
      this detection. The annotation is well corroborated.
    supported_by:
    - reference_id: PMID:21630459
      supporting_text: >-
        With this approach, 403 different proteins have been identified from the
        isolated sperm nuclei. The most abundant family of proteins identified
        are the histones, for which several novel members had not been reported
        previously as present in the spermatogenic cell line or in the human
        mature spermatozoa.
    - reference_id: PMID:21231916
      supporting_text: >-
        Overexpressed chaperones that suppressed polyQ aggregation were found not
        to be able to stimulate luciferase refolding.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:23612975
  review:
    summary: >-
      IDA annotation for protein folding (GO:0006457) from Gillis et al.
      (PMID:23612975). The GOA qualifier is 'acts_upstream_of_or_within', which
      indicates involvement in the broader process. Gillis et al. demonstrated
      that DNAJB8 prevents intracellular aggregation of polyQ peptides by
      directly binding the polyQ tract, placing it in the protein folding quality
      control pathway. DNAJB8 functions as a holdase rather than a foldase --
      Hageman et al. (PMID:21231916) showed that chaperones suppressing polyQ
      aggregation could not stimulate luciferase refolding. The term protein
      folding is therefore somewhat imprecise for DNAJB8, but the broader
      proteostasis role is real and the qualifier 'acts_upstream_of_or_within'
      appropriately captures the indirect relationship.
    action: ACCEPT
    reason: >-
      DNAJB8 is a J-domain co-chaperone that participates in protein folding
      quality control, specifically by preventing aggregation of misfolded
      proteins. The qualifier 'acts_upstream_of_or_within' is appropriate as
      DNAJB8 acts within the protein folding process by suppressing aggregation
      rather than directly catalyzing productive folding. The IDA evidence from
      Gillis et al. (PMID:23612975) directly demonstrates this anti-aggregation
      activity in cellular assays with polyQ peptides.
    supported_by:
    - reference_id: PMID:23612975
      supporting_text: >-
        we expressed polyQ peptides in cells and show that their intracellular
        aggregation is prevented by DNAJB6 and DNAJB8, members of the DNAJ
        (Hsp40) chaperone family. In contrast, HSPA/Hsp70 and DNAJB1, also
        members of the DNAJ chaperone family, did not prevent peptide-initiated
        aggregation.
    - 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:0044183
    label: protein folding chaperone
  evidence_type: IDA
  original_reference_id: PMID:23612975
  review:
    summary: >-
      IDA annotation for protein folding chaperone (GO:0044183) from Gillis et
      al. (PMID:23612975). This study demonstrated that DNAJB8 prevents
      intracellular aggregation of polyQ peptides by directly binding the polyQ
      tract, establishing DNAJB8 as a chaperone that binds proteins to assist
      in the protein folding process (by preventing misfolding/aggregation).
      Hageman et al. (PMID:20159555) previously established that DNAJB8 is a
      superior suppressor of polyQ protein aggregation with activity residing
      in the C-terminal serine-rich region. This is a core molecular function
      of DNAJB8 and GO:0044183 is the best available GO term for its holdase
      chaperone activity.
    action: ACCEPT
    reason: >-
      GO:0044183 (protein folding chaperone) is the most appropriate molecular
      function term for DNAJB8. The IDA evidence from Gillis et al.
      (PMID:23612975) directly demonstrates that DNAJB8 binds polyQ substrates
      to prevent their aggregation, which falls within the scope of this term.
      This is also the recommended replacement term for the obsoleting
      GO:0051082 (unfolded protein binding). The annotation is independently
      supported by IBA phylogenetic inference for the same term.
    additional_reference_ids:
    - PMID:20159555
    supported_by:
    - reference_id: PMID:23612975
      supporting_text: >-
        we conclude that the mechanism of DNAJB6 and DNAJB8 is suppression of
        polyQ protein aggregation by directly binding the polyQ tract.
    - reference_id: PMID:20159555
      supporting_text: >-
        members of a subclass of the DNAJB family (particularly DNAJB6b and
        DNAJB8) are superior suppressors of aggregation and toxicity of
        disease-associated polyglutamine proteins. The antiaggregation activity
        is largely independent of the N-terminal Hsp70-interacting J-domain.
core_functions:
- description: >-
    Holdase chaperone that potently suppresses aggregation of polyglutamine-
    expanded proteins and other aggregation-prone substrates. DNAJB8 uses at
    least two distinct substrate-binding modes: (1) a serine-rich stretch in the
    S/T-rich region for fibrillar/amyloid aggregation suppression by directly
    binding the polyQ tract, and (2) a separate C-terminal TTK-LKS motif for
    amorphous inclusion suppression via Hsp70-dependent proteasomal degradation
    (DOI:10.1242/jcs.255596). The anti-aggregation activity is largely
    independent of the N-terminal J-domain/HSP70-stimulating activity and
    requires interaction with histone deacetylases (HDAC4, HDAC6, SIRT2)
    (PMID:20159555). A key regulatory mechanism is an intramolecular JD-CTD
    interaction that sequesters the J-domain surface and controls Hsp70
    recruitment as a reversible switch (DOI:10.1038/s41467-021-21147-x).
    DNAJB8 self-assembles into oligomeric puncta via an AFSSFN (147-152)
    steric-zipper motif (resolved at 0.75 angstrom by MicroED), but
    oligomerization is dispensable for substrate binding and anti-aggregation
    function (DOI:10.1016/j.str.2024.02.015). DNAJB8 cannot stimulate
    luciferase refolding, distinguishing its holdase mechanism from foldase-type
    chaperones (PMID:21231916).
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  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:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:20159555
    supporting_text: >-
      members of a subclass of the DNAJB family (particularly DNAJB6b and
      DNAJB8) are superior suppressors of aggregation and toxicity of
      disease-associated polyglutamine proteins. The antiaggregation activity
      is largely independent of the N-terminal Hsp70-interacting J-domain.
      Rather, a C-terminal serine-rich (SSF-SST) region and the C-terminal
      tail are essential.
  - reference_id: PMID:23612975
    supporting_text: >-
      we conclude that the mechanism of DNAJB6 and DNAJB8 is suppression of
      polyQ protein aggregation by directly binding the polyQ tract.
  - 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.
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:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:20159555
  title: A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic
    protein aggregation.
  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:23612975
  title: The DNAJB6 and DNAJB8 protein chaperones prevent intracellular aggregation
    of polyglutamine peptides.
  findings: []
- id: DOI:10.1016/j.str.2024.02.015
  title: DNAJB8 oligomerization is mediated by an aromatic-rich motif that is
    dispensable for substrate activity.
  findings:
    - statement: >-
        AFSSFN (147-152) steric-zipper motif resolved at 0.75 angstrom by MicroED
        as a class 6 steric zipper stabilized by aromatic interactions (F148, F151);
        F151 is a primary driver of full-length DNAJB8 self-assembly.
    - statement: >-
        Engineered monomeric DNAJB8 variants retain substrate binding and
        anti-aggregation function, demonstrating oligomerization is mechanistically
        separable from chaperone activity.
- id: DOI:10.1038/s41467-021-21147-x
  title: Regulatory inter-domain interactions influence Hsp70 recruitment to the
    DnaJB8 chaperone.
  findings:
    - statement: >-
        Intramolecular JD-CTD interaction sequesters the J-domain surface,
        preventing Hsp70 interaction as a reversible regulatory switch controlling
        Hsp70 recruitment.
    - statement: >-
        DNAJB8-Clover forms juxtanuclear puncta in 39.2 +/- 3.1% of cells vs
        0.44 +/- 0.50% for Clover control.
- id: DOI:10.1242/jcs.255596
  title: DNAJB chaperones suppress destabilised protein aggregation via a region
    distinct from that used to inhibit amyloidogenesis.
  findings:
    - statement: >-
        Distinct substrate-binding modes in DNAJB8: serine-rich stretch needed
        for fibrillar/amyloid aggregation suppression but not for FlucDM inclusion
        suppression; a separate CTD TTK-LKS motif is required for amorphous
        inclusion suppression via Hsp70-dependent proteasomal degradation.
- id: DOI:10.1158/0008-5472.CAN-11-3062
  title: HSP DNAJB8 controls tumor-initiating ability in renal cancer stem-like
    cells.
  findings:
    - statement: >-
        DNAJB8 preferentially expressed in renal cancer stem-like/cancer-initiating
        cell populations; overexpression increases side population fraction and
        tumor-initiating ability.
- id: DOI:10.1038/s41419-022-04599-x
  title: DNAJB8 in small extracellular vesicles promotes oxaliplatin resistance
    through TP53/MDR1 pathway in colon cancer.
  findings:
    - statement: >-
        DNAJB8 interacts with TP53 and inhibits TP53 ubiquitination, stabilizing
        TP53 and leading to MDR1/P-gp upregulation and increased oxaliplatin
        resistance; sEV-mediated transfer propagates resistance.
- id: DOI:10.1038/s41416-020-1017-1
  title: Development of an artificial antibody specific for HLA/peptide complex
    derived from cancer stem-like cell/cancer-initiating cell antigen DNAJB8.
  findings:
    - statement: >-
        Engineered antibodies targeting HLA-A24/DNAJB8-derived peptide complex
        achieve nanomolar affinity (KD 2.96-5.04 nM) and mediate CDC and
        bispecific antibody-dependent cellular cytotoxicity.