id: P25686
gene_symbol: DNAJB2
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  DNAJB2 (also known as HSJ1) is a neuronally enriched class B J-domain protein (HSP40 co-chaperone)
  that functions as a "triage" co-chaperone for HSP70/Hsc70, coupling chaperone recognition of
  misfolded proteins to ubiquitin-dependent proteasomal degradation. Its domain architecture
  comprises an N-terminal J domain (with conserved HPD motif) that stimulates HSP70 ATPase
  activity, a G/F-rich region, and two C-terminal ubiquitin-interacting motifs (UIMs) that bind
  polyubiquitin chains and facilitate client delivery to the proteasome. DNAJB2 cooperates with
  the E3 ubiquitin ligase CHIP/STUB1 and protects polyubiquitin chains from deubiquitylation,
  supporting a "shuttle" function for ubiquitinated clients destined for proteasomal degradation
  (DOI:10.3390/ijms21041409). CK2 phosphorylation of UIM2 (Ser250) modulates ubiquitin-binding
  capacity, providing a kinase-dependent regulatory mechanism (PMID:28031292). DNAJB2 exists as
  two alternatively spliced isoforms: the ER-membrane-anchored HSJ1b (isoform 1, ~324 aa,
  geranylgeranylated) and the cytoplasmic/nuclear HSJ1a (isoform 2, ~277 aa). DNAJB2
  suppresses aggregation of diverse neurodegeneration-associated proteins including polyQ-expanded
  huntingtin, SOD1, TDP-43, and parkin variants (DOI:10.3389/fncel.2014.00191). Mutations in
  DNAJB2 cause autosomal recessive distal hereditary motor neuropathy (dHMN/CMT2), and a first
  dominant mutation was reported in 2023: a stop-loss extension (p.*278Glyext*83) that creates a
  transmembrane helix driving ER mislocalization and proteasomal degradation of the mutant protein
  (DOI:10.1093/hmg/ddad058). The disease spectrum has expanded to include both recessive and
  dominant neuromyopathy and distal myopathy (DOI:10.1097/WCO.0000000000001299). Cystamine (150
  uM) has been shown to increase DNAJB2 levels in patient fibroblasts, suggesting a potential
  pharmacologic approach (DOI:10.3390/neurolint17050073).
alternative_products:
- name: 1 (HSJ1b {ECO:0000303|PubMed:1599432})
  id: P25686-3
- name: 2 (HSJ1a {ECO:0000303|PubMed:1599432}, DNAJB2a)
  id: P25686-2
  sequence_note: VSP_001286, VSP_001287
existing_annotations:
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      DNAJB2 (HSJ1) stimulates the ATPase activity of HSP70/Hsc70 via its conserved J domain.
      Cheetham et al. (1994) showed that both HSJ1a and HSJ1b enhance the weak intrinsic ATPase
      activity of constitutive Hsc70 more than fivefold (PMID:7957263). Gao et al. (2012) confirmed
      that the J domain of HSJ1a mediates interaction with and ATPase activation of HSP70 (PMID:22219199).
      The IBA annotation is phylogenetically sound for J-domain proteins, and the term accurately
      captures a core molecular function of DNAJB2.
    action: ACCEPT
    reason: >-
      ATPase activator activity is a well-established core function of DNAJB2 as a J-domain
      co-chaperone. Multiple experimental studies confirm this function (PMID:7957263, PMID:22219199).
      The IBA annotation is consistent with the conserved role of the J domain across the DnaJ family.
    supported_by:
      - reference_id: PMID:7957263
        supporting_text: >-
          The weak intrinsic ATPase activity of the constitutive 70-kDa heat-shock protein
          is enhanced more than fivefold by stoichiometric amounts of both HSJ1a and HSJ1b.
      - reference_id: PMID:22219199
        supporting_text: >-
          The J domain of HSJ1a shares a conserved structure with other J domains from both
          eukaryotic and prokaryotic species, and it mediates the interaction with and the
          ATPase cycle of HSP70.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      DNAJB2 isoform 2 (HSJ1a) is cytoplasmic/cytosolic (PMID:12754272). UniProt confirms that
      isoform 2 localizes to cytoplasm. Hageman et al. (2011) showed cytosolic localization by
      immunofluorescence (PMID:21231916). The IBA annotation to cytosol is appropriate as HSJ1a
      is the primary cytosolic isoform. Note that isoform 1 (HSJ1b) is ER-membrane anchored.
    action: ACCEPT
    reason: >-
      Cytosol is a well-supported localization for DNAJB2 isoform HSJ1a. Multiple experimental
      studies (PMID:12754272, PMID:21231916) confirm cytoplasmic/cytosolic localization. The IBA
      annotation is phylogenetically reasonable for J-domain proteins.
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding genes
          and most of the corresponding proteins are localized in the cytosol.
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      DNAJB2 physically interacts with HSP70 family members through its J domain. Cheetham et al.
      (1994) demonstrated in vitro interaction between HSJ1a/HSJ1b and constitutive Hsc70
      (PMID:7957263). Gao et al. (2012) confirmed the J domain of HSJ1a binds HSP70 and determined
      the structural basis for this interaction (PMID:22219199). UniProt records interactions with
      HSPA1A, HSPA1B, and HSPA8 (Hsc70). The IBA annotation is well-supported for all J-domain
      proteins and represents a core function of DNAJB2.
    action: ACCEPT
    reason: >-
      Hsp70 protein binding is a fundamental and experimentally validated function of DNAJB2.
      Multiple studies confirm the J-domain-mediated physical interaction with HSP70/Hsc70
      (PMID:7957263, PMID:22219199, PMID:21625540). This is a core molecular function.
    supported_by:
      - reference_id: PMID:22219199
        supporting_text: >-
          The J-domain co-chaperones work together with the heat shock protein 70 (HSP70)
          chaperone to regulate many cellular events, but the mechanism underlying the
          J-domain-mediated HSP70 function remains elusive.
      - reference_id: PMID:7957263
        supporting_text: >-
          The weak intrinsic ATPase activity of the constitutive 70-kDa heat-shock protein
          is enhanced more than fivefold by stoichiometric amounts of both HSJ1a and HSJ1b.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      DNAJB2 participates in protein refolding as part of the HSP70 chaperone machine. Hageman
      et al. (2011) systematically assessed HSP40/DNAJ family members for refolding of heat-denatured
      luciferase and suppression of polyQ aggregation (PMID:21231916). DNAJB2 showed chaperone-like
      activities in these assays. The IBA annotation to protein refolding is phylogenetically
      reasonable for J-domain proteins that assist HSP70 in protein refolding.
    action: ACCEPT
    reason: >-
      Protein refolding is a well-characterized function of DNAJB2 as an HSP70 co-chaperone.
      Experimental data from Hageman et al. (2011) support this annotation (PMID:21231916), and
      the IBA phylogenetic inference is sound for J-domain co-chaperones.
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding genes
          and most of the corresponding proteins are localized in the cytosol. To test for possible
          functional differences and/or substrate specificity, we assessed the effect of
          overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the
          suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin
          fragment.
- term:
    id: GO: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). DNAJB2 is a
      J-domain containing HSP40 co-chaperone that functions by binding to misfolded/unfolded proteins
      in the context of the HSP70 chaperone machine, not as an independent unfolded protein binder.
      The IBA annotation via PANTHER is phylogenetically reasonable for J-domain proteins in general,
      but the term itself is being replaced. The correct replacement is GO:0044183 (protein folding
      chaperone), which accurately captures DNAJB2's role in assisting protein folding as an HSP70
      co-chaperone. UniProt describes it as functioning as a co-chaperone that regulates substrate
      binding and activates ATPase activity of HSP70 family chaperones (PMID:22219199, PMID:7957263).
      Hageman et al. (2011) showed DNAJB2 has chaperone-like activities including protein refolding
      and suppression of aggregation (PMID:21231916).
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. DNAJB2 functions as a protein folding chaperone (HSP70
      co-chaperone) via its J domain, not as a standalone unfolded protein binder. GO:0044183
      (protein folding chaperone) is the appropriate replacement term, as it captures the functional
      role of binding to proteins to assist the folding process.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    additional_reference_ids:
      - PMID:21231916
      - PMID:7957263
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding genes
          and most of the corresponding proteins are localized in the cytosol. To test for possible
          functional differences and/or substrate specificity, we assessed the effect of
          overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the
          suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin
          fragment.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      This IEA annotation derives from UniProtKB subcellular location vocabulary mapping. UniProt
      records that isoform 2 (HSJ1a) localizes to the nucleus (PMID:12754272). Chapple and Cheetham
      (2003) showed nuclear localization for HSJ1a, and Hageman et al. (2011) confirmed nucleus
      localization by IDA (PMID:21231916). The IEA mapping is consistent with experimental data.
      HSJ1a is found in both cytoplasm and nucleus.
    action: ACCEPT
    reason: >-
      Nuclear localization of DNAJB2 isoform HSJ1a is experimentally supported by IDA evidence
      (PMID:21231916, PMID:12754272). The IEA annotation correctly reflects the UniProt subcellular
      location entry. This is a broader IEA that is acceptable alongside the more specific IDA
      evidence.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      This IEA annotation from combined automated methods maps DNAJB2 to cytoplasm. UniProt records
      isoform 2 (HSJ1a) in the cytoplasm (PMID:12754272, PMID:21625540). This is a broader
      localization term compared to cytosol (GO:0005829), and is correct for HSJ1a. The IEA
      annotation is consistent with experimental data.
    action: ACCEPT
    reason: >-
      Cytoplasm localization is experimentally confirmed for DNAJB2 isoform HSJ1a (PMID:12754272,
      PMID:21625540). Although cytosol (GO:0005829) is more specific and also annotated, this
      broader IEA annotation is acceptable.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      This IEA annotation maps from UniProt subcellular location vocabulary. UniProt records that
      isoform 1 (HSJ1b) localizes to the endoplasmic reticulum membrane via C-terminal
      geranylgeranylation at Cys-321, on the cytoplasmic side (PMID:12754272). Chapple and Cheetham
      (2003) showed that HSJ1b is anchored to the ER membrane and that mutation of C321S causes
      relocalization. This annotation is isoform-specific to HSJ1b but is appropriately captured
      for the gene product.
    action: ACCEPT
    reason: >-
      ER membrane localization is experimentally confirmed for DNAJB2 isoform HSJ1b via
      geranylgeranylation (PMID:12754272). The IEA annotation correctly reflects the UniProt
      subcellular location. While isoform-specific, this is a valid annotation for the gene product.
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      This IEA annotation derives from InterPro domain mapping (IPR043183, DNJB2/6-like domain).
      HSP70 protein binding is a core function of DNAJB2 mediated by the J domain. This is well
      supported by multiple experimental studies (PMID:7957263, PMID:22219199, PMID:21625540).
      The InterPro mapping is correct.
    action: ACCEPT
    reason: >-
      The InterPro-derived IEA annotation to Hsp70 protein binding is accurate for DNAJB2 as
      a J-domain protein. This is experimentally validated (PMID:7957263, PMID:22219199) and
      represents a core molecular function.
- 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 is based on InterPro mapping (IPR043183, the DNJB2/6-like domain). DNAJB2 is
      classified as a J-domain protein / HSP40 co-chaperone whose function is to assist HSP70
      in protein folding, not to independently bind unfolded proteins. The InterPro-derived mapping
      should be updated to reflect the replacement term GO:0044183 (protein folding chaperone),
      which accurately describes the chaperone function of J-domain proteins.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. The IEA annotation from InterPro (IPR043183) correctly
      identifies DNAJB2 as having a DNJB2/6-like domain associated with chaperone function, but the
      target term should be updated to GO:0044183 (protein folding chaperone), which better captures
      the co-chaperone role of J-domain proteins in assisting protein folding.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    supported_by:
      - reference_id: PMID:24023695
        supporting_text: >-
          The molecular chaperone HSJ1 (DNAJB2) is a member of the Hsp40 (or DnaJ) family of heat
          shock proteins that contain a J domain, which is crucial in substrate recognition by
          Hsp70 [21], [22], [23]. Thus, Hsp40/DnaJ protein function is essential for Hsp70
          function, including protein folding and directing misfolded proteins towards the
          proteasome [23].
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      This IEA annotation from ARBA machine learning (GO_REF:0000117) maps DNAJB2 to protein-folding
      chaperone binding. DNAJB2 binds HSP70 family chaperones (HSPA1A, HSPA1B, HSPA8) via its J domain
      (PMID:7957263, PMID:22219199, PMID:21625540). HSP70 proteins are protein-folding chaperones,
      so this annotation is accurate. There is also IPI evidence for this same term (PMID:21231916).
    action: ACCEPT
    reason: >-
      The IEA annotation is consistent with DNAJB2's well-characterized binding to HSP70 chaperones.
      Experimentally confirmed by multiple studies and also annotated with IPI evidence.
- term:
    id: GO:0090084
    label: negative regulation of inclusion body assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      This IEA annotation from ARBA machine learning captures DNAJB2's role in suppressing protein
      aggregation and inclusion body formation. Multiple studies show that HSJ1a suppresses inclusion
      formation by polyglutamine-expanded proteins (PMID:21231916) and mutant SOD1 (PMID:24023695).
      There is also IDA evidence for the same term (PMID:21231916). The automated annotation is
      consistent with experimentally demonstrated function.
    action: ACCEPT
    reason: >-
      Negative regulation of inclusion body assembly is well supported by experimental evidence
      (PMID:21231916, PMID:24023695). DNAJB2 reduces inclusion formation through its J domain and
      UIM domain activities. The IEA annotation is consistent with IDA evidence.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  review:
    summary: >-
      This IPI annotation from Taipale et al. (2014) derives from a large-scale chaperone interaction
      network study. The with/from column indicates interaction with MLF1 (P58340). While the
      interaction may be real, GO:0005515 (protein binding) is uninformative and does not specify the
      nature of the interaction. DNAJB2 has more specific binding annotations (Hsp70 protein binding,
      ubiquitin binding, protein-folding chaperone binding) that are more informative.
    action: REMOVE
    reason: >-
      Protein binding (GO:0005515) is uninformative for DNAJB2. More specific molecular function
      binding terms are already annotated (GO:0030544 Hsp70 protein binding, GO:0043130 ubiquitin
      binding, GO:0051087 protein-folding chaperone binding). Per curation guidelines, this vague
      term should be replaced by more informative annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      This IPI annotation from Huttlin et al. (2021) BioPlex proteome-scale interactome study
      (with/from MLF1, P58340). As with the other protein binding annotation, GO:0005515 is
      uninformative. More specific binding terms already capture DNAJB2's binding functions.
    action: REMOVE
    reason: >-
      Protein binding (GO:0005515) is uninformative. More specific molecular function binding terms
      are already annotated for DNAJB2. This vague annotation does not add functional information.
- term:
    id: GO:0031965
    label: nuclear membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      This IDA annotation from HPA (Human Protein Atlas) immunofluorescence data places DNAJB2 at
      the nuclear membrane. UniProt records that isoform 2 (HSJ1a) localizes to cytoplasm and
      nucleus (PMID:12754272). Nuclear membrane localization is plausible but not specifically
      described in the primary literature for DNAJB2. The HPA immunofluorescence may be detecting
      perinuclear ER-associated HSJ1b or nuclear-peripheral HSJ1a. This is not a well-characterized
      localization for DNAJB2 in the literature.
    action: UNDECIDED
    reason: >-
      Nuclear membrane localization comes from HPA immunofluorescence data (GO_REF:0000052),
      not from primary DNAJB2 literature. While DNAJB2 is found in nucleus and ER membrane, nuclear
      membrane specifically is not discussed in the primary literature. Without access to the HPA
      images or detailed characterization, this cannot be fully evaluated.
- term:
    id: GO:0120283
    label: protein serine/threonine kinase binding
  evidence_type: IPI
  original_reference_id: PMID:28031292
  review:
    summary: >-
      Ottaviani et al. (2017) showed that CK2 (protein kinase CK2, comprising CSNK2A1/P68400 and
      CSNK2A2/P19784 catalytic subunits) phosphorylates DNAJB2 at Ser250 and Ser247 within its
      UIM2 domain (PMID:28031292). The GOA with/from column lists P19784 (CSNK2A2) and P68400
      (CSNK2A1). CK2 is a serine/threonine kinase, so the annotation to protein serine/threonine
      kinase binding accurately captures the demonstrated physical interaction.
    action: ACCEPT
    reason: >-
      DNAJB2 is a confirmed substrate of CK2. Ottaviani et al. (2017) demonstrated direct
      phosphorylation and physical interaction between CK2 and HSJ1 in vitro and in cells
      (PMID:28031292). The term accurately describes the interaction.
    supported_by:
      - reference_id: PMID:28031292
        supporting_text: >-
          Here we show that CK2, a ubiquitous and constitutively active protein kinase,
          phosphorylates HSJ1 within its second UIM, at the dominant site Ser250 and the
          hierarchical site Ser247.
- term:
    id: GO:0140318
    label: protein transporter activity
  evidence_type: TAS
  original_reference_id: PMID:28031292
  review:
    summary: >-
      This TAS annotation from ARUK-UCL references PMID:28031292 (Ottaviani et al. 2017). The paper
      describes DNAJB2 as a "shuttling factor to sort chaperone clients to the proteasome" (citing
      Westhoff et al. 2005, PMID:15936278). DNAJB2 facilitates delivery of ubiquitylated misfolded
      proteins to the proteasome. However, "protein transporter activity" (GO:0140318) implies a
      transporter function, which is a stretch for a co-chaperone that helps target substrates for
      proteasomal degradation. This is more accurately described as regulation of proteasomal
      targeting rather than transport per se.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      DNAJB2 acts as a co-chaperone that sorts misfolded clients to the proteasome, but this is
      more accurately described as chaperoning/targeting rather than transport activity. The term
      protein transporter activity implies a direct transport mechanism that is not well-supported
      for DNAJB2. The proteasomal targeting function is better captured by annotations like
      GO:0032436 (positive regulation of proteasomal ubiquitin-dependent protein catabolic process).
    supported_by:
      - reference_id: PMID:28031292
        supporting_text: >-
          HSJ1 (also known as DNAJB2) is a key component in neuronal protein quality control.
          It is a molecular chaperone that is preferentially expressed in neurons that can act
          as a shuttling factor to sort chaperone clients to the proteasome (1).
- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein catabolic
      process
  evidence_type: TAS
  original_reference_id: PMID:28031292
  review:
    summary: >-
      This TAS annotation captures DNAJB2's role in promoting proteasomal degradation of
      ubiquitylated client proteins. Ottaviani et al. (2017) describe HSJ1 as binding ubiquitylated
      proteins through its UIMs and facilitating their delivery to the proteasome (PMID:28031292).
      Westhoff et al. (2005) showed HSJ1 acts as a shuttling factor for sorting chaperone clients
      to the proteasome (PMID:15936278). Gao et al. (2011) demonstrated HSJ1a promotes HSP70-mediated
      proteasomal degradation of ataxin-3 (PMID:21625540). This is a core function of DNAJB2.
    action: ACCEPT
    reason: >-
      Positive regulation of proteasomal ubiquitin-dependent protein catabolism is a well-characterized
      core function of DNAJB2, mediated through its UIM domains that bind ubiquitylated substrates
      and its J domain that engages HSP70. Multiple studies confirm this (PMID:28031292, PMID:15936278,
      PMID:21625540, PMID:24023695).
    supported_by:
      - reference_id: PMID:28031292
        supporting_text: >-
          It binds ubiquitylated proteins through its Ubiquitin Interacting Motifs (UIMs) and
          facilitates their delivery to the proteasome for degradation.
      - reference_id: PMID:21625540
        supporting_text: >-
          The J-domain down-regulates the protein level of Atx3 through HSP70 mediated proteasomal
          degradation, while the UIM domain may alleviate this process via maintaining the
          ubiquitinated Atx3.
- term:
    id: GO:0043130
    label: ubiquitin binding
  evidence_type: IDA
  original_reference_id: PMID:28031292
  review:
    summary: >-
      DNAJB2 contains two ubiquitin-interacting motifs (UIMs) that bind ubiquitin chains. Ottaviani
      et al. (2017) directly demonstrated ubiquitin binding through co-immunoprecipitation of
      HSJ1a-associated ubiquitylated proteins, and showed that CK2 phosphorylation of the UIM2
      domain reduces this binding (PMID:28031292). Gao et al. (2011) showed UIM domains bind K48-
      and K63-linked diubiquitin chains, with UIM2 being more important (PMID:21625540). Westhoff
      et al. (2005) showed UIM mutation abolishes polyubiquitin chain binding (PMID:15936278).
      However, the more specific term GO:0031593 (polyubiquitin modification-dependent protein
      binding) or GO:0140036 (ubiquitin-modified protein reader activity) may be more appropriate,
      as DNAJB2 specifically reads ubiquitin modifications on client proteins.
    action: ACCEPT
    reason: >-
      Ubiquitin binding via UIM domains is a core function of DNAJB2 directly demonstrated by
      IDA evidence (PMID:28031292). While more specific terms exist, this annotation is accurate
      and supported by multiple studies.
    supported_by:
      - reference_id: PMID:28031292
        supporting_text: >-
          Near the C-terminus HSJ1 has two Ubiquitin Interacting Motifs (UIMs), that function
          to bind ubiquitin chains and help prevent client protein aggregation.
- term:
    id: GO:0070050
    label: neuron cellular homeostasis
  evidence_type: TAS
  original_reference_id: PMID:28031292
  review:
    summary: >-
      This TAS annotation from ARUK-UCL references PMID:28031292. Ottaviani et al. (2017) describe
      HSJ1 as "a key component in neuronal protein quality control" and note that DNAJB2 mutations
      cause hereditary neuropathies (PMID:28031292). DNAJB2 is preferentially expressed in neurons
      and maintains proteostasis there. However, "neuron cellular homeostasis" (GO:0070050) is a
      very broad biological process term. DNAJB2's role is specifically in protein quality control
      and proteostasis in neurons, not in all aspects of neuronal homeostasis.
    action: KEEP_AS_NON_CORE
    reason: >-
      While DNAJB2 is clearly important for neuronal protein homeostasis (mutations cause
      neuropathy), the term "neuron cellular homeostasis" is broad. DNAJB2's contribution is
      specifically through protein quality control. This is a downstream consequence of its core
      chaperone/ubiquitin-binding functions rather than a direct molecular activity.
    supported_by:
      - reference_id: PMID:28031292
        supporting_text: >-
          HSJ1 (also known as DNAJB2) is a key component in neuronal protein quality control.
          It is a molecular chaperone that is preferentially expressed in neurons that can act
          as a shuttling factor to sort chaperone clients to the proteasome (1).
- term:
    id: GO:0140036
    label: ubiquitin-modified protein reader activity
  evidence_type: IDA
  original_reference_id: PMID:28031292
  review:
    summary: >-
      DNAJB2 reads ubiquitin modifications on client proteins via its two UIM domains and sorts
      them for proteasomal degradation. Ottaviani et al. (2017) showed by co-immunoprecipitation
      that HSJ1a binds ubiquitylated clients, and this binding is reduced by CK2 phosphorylation
      of UIM2 or by UIM-disrupting mutations (PMID:28031292). This term captures the specific
      activity of recognizing ubiquitin modifications to direct protein fate, which is more
      precise than simple ubiquitin binding.
    action: ACCEPT
    reason: >-
      Ubiquitin-modified protein reader activity precisely describes DNAJB2's UIM-mediated
      recognition of ubiquitylated substrates for proteasomal targeting. This is experimentally
      confirmed by IDA evidence (PMID:28031292) and represents a core molecular function that
      distinguishes DNAJB2 from other J-domain proteins.
    supported_by:
      - reference_id: PMID:28031292
        supporting_text: >-
          It binds ubiquitylated proteins through its Ubiquitin Interacting Motifs (UIMs) and
          facilitates their delivery to the proteasome for degradation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21625540
  review:
    summary: >-
      This IPI annotation from Gao et al. (2011) records DNAJB2 self-interaction (with/from
      P25686-2, HSJ1a isoform). The paper shows HSJ1a interaction with HSP70 and ataxin-3, and
      the with/from suggesting self-interaction may reflect co-immunoprecipitation artifacts.
      Regardless, GO:0005515 (protein binding) is uninformative. DNAJB2's interactions are
      better captured by specific binding terms already annotated.
    action: REMOVE
    reason: >-
      Protein binding (GO:0005515) is uninformative. DNAJB2's specific binding interactions are
      already captured by GO:0030544 (Hsp70 protein binding), GO:0043130 (ubiquitin binding),
      GO:0051087 (protein-folding chaperone binding), and GO:0140036 (ubiquitin-modified protein
      reader activity).
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: IGI
  original_reference_id: PMID:9553041
  review:
    summary: >-
      This IGI annotation from Maheswaran et al. (1998) derives from a study of the Wilms tumor
      suppressor WT1, not DNAJB2 specifically. The paper showed that WT1-mediated growth
      inhibition requires association with Hsp70, and that substitution of a heterologous
      Hsp70-binding domain derived from "human DNAJ" could restore WT1 function (PMID:9553041).
      This is a chimeric construct experiment; the J domain of an unspecified human DnaJ protein
      was fused to WT1 to test whether Hsp70 binding mediates growth suppression. DNAJB2 is not
      the gene under study, and the observation is about WT1 function, not DNAJB2 function.
    action: REMOVE
    reason: >-
      PMID:9553041 studies WT1 tumor suppressor function, not DNAJB2. The paper used a generic
      "human DNAJ" domain as a tool to provide Hsp70-binding capability to WT1. Negative regulation
      of cell proliferation is not a function of DNAJB2; it is a function of WT1. The IGI annotation
      incorrectly attributes a WT1 phenotype to DNAJB2.
    supported_by:
      - reference_id: PMID:9553041
        supporting_text: >-
          Substitution of a heterologous Hsp70-binding domain derived from human DNAJ is
          sufficient to restore the functional properties of a WT1 protein with an amino-terminal
          deletion, an effect that is abrogated by a point mutation in DNAJ that reduces binding
          to Hsp70.
- term:
    id: GO:0030308
    label: negative regulation of cell growth
  evidence_type: IGI
  original_reference_id: PMID:9553041
  review:
    summary: >-
      Same as the GO:0008285 annotation above - this IGI annotation from Maheswaran et al. (1998)
      derives from a WT1 study where a human DNAJ J domain was used as a chimeric tool. The growth
      inhibition is a property of WT1, not DNAJB2. DNAJB2's J domain was used merely to provide
      Hsp70-binding capability to test WT1 function.
    action: REMOVE
    reason: >-
      PMID:9553041 is about WT1 function, not DNAJB2. The DNAJ J domain was used as a heterologous
      tool in a chimeric construct. Negative regulation of cell growth is a WT1 function, not a
      DNAJB2 function. This annotation incorrectly attributes a WT1 phenotype to DNAJB2.
    supported_by:
      - reference_id: PMID:9553041
        supporting_text: >-
          Substitution of a heterologous Hsp70-binding domain derived from human DNAJ is
          sufficient to restore the functional properties of a WT1 protein with an amino-terminal
          deletion, an effect that is abrogated by a point mutation in DNAJ that reduces binding
          to Hsp70.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:21231916
  review:
    summary: >-
      This IPI annotation from Hageman et al. (2011) is based on the demonstrated interaction
      between DNAJB2 and HSP70 family members (with/from P0DMV8/HSPA1A, P0DMV9/HSPA1B,
      P17066/HSPA6). The study systematically characterized interactions between HSP40/DNAJ
      and HSP70/HSPA family members and demonstrated that DNAJB2 interacts with HSP70 proteins
      that are protein-folding chaperones (PMID:21231916). This is a core molecular function.
    action: ACCEPT
    reason: >-
      Protein-folding chaperone binding is experimentally validated by co-expression studies
      showing DNAJB2 interaction with HSP70 chaperones HSPA1A, HSPA1B, and HSPA6 (PMID:21231916).
      This is a core function of DNAJB2 as a J-domain co-chaperone.
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding genes
          and most of the corresponding proteins are localized in the cytosol. To test for possible
          functional differences and/or substrate specificity, we assessed the effect of
          overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the
          suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin
          fragment.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IMP
  original_reference_id: PMID:24023695
  review:
    summary: >-
      This IMP annotation from Novoselov et al. (2013) is based on data showing that HSJ1a
      overexpression reduces SOD1(G93A) aggregation and improves motor neuron survival in vivo
      (PMID:24023695). The J domain mutant H31Q lost the ability to suppress aggregation while
      the UIM mutant was partially functional. The paper describes HSJ1a as acting through
      "chaperone, co-chaperone and pro-ubiquitylation activity." Protein folding is an appropriate
      biological process for DNAJB2's role in maintaining protein homeostasis.
    action: ACCEPT
    reason: >-
      Protein folding is a core biological process for DNAJB2 as an HSP70 co-chaperone. The IMP
      evidence from mutant phenotype studies (J domain and UIM mutants affecting SOD1 aggregation)
      supports DNAJB2's role in protein folding/quality control (PMID:24023695).
    supported_by:
      - reference_id: PMID:24023695
        supporting_text: >-
          HSJ1a preferentially bound to mutant SOD1, enhanced SOD1 ubiquitylation and reduced SOD1
          aggregation in a J-domain and ubiquitin interaction motif (UIM) dependent manner.
          Collectively, the data suggest that HSJ1a acts on mutant SOD1 through a combination of
          chaperone, co-chaperone and pro-ubiquitylation activity.
- term:
    id: GO:0031396
    label: regulation of protein ubiquitination
  evidence_type: IMP
  original_reference_id: PMID:24023695
  review:
    summary: >-
      This IMP annotation from Novoselov et al. (2013) is based on data showing that HSJ1a
      enhances SOD1 ubiquitylation in a UIM-dependent manner (PMID:24023695). The UIM mutant did
      not enhance SOD1 ubiquitylation, while wild-type HSJ1a strongly increased ubiquitin
      immunoreactivity on SOD1 upon proteasome inhibition. Gao et al. (2011) also showed HSJ1a
      regulates ubiquitination of ataxin-3 (PMID:21625540). This is a core function linked to
      DNAJB2's UIM domains.
    action: ACCEPT
    reason: >-
      Regulation of protein ubiquitination is a well-characterized function of DNAJB2 mediated
      by its UIM domains. IMP evidence from mutant studies confirms this (PMID:24023695,
      PMID:21625540). This is a core biological process for DNAJB2.
    supported_by:
      - reference_id: PMID:24023695
        supporting_text: >-
          HSJ1a preferentially bound to mutant SOD1, enhanced SOD1 ubiquitylation and reduced SOD1
          aggregation in a J-domain and ubiquitin interaction motif (UIM) dependent manner.
      - reference_id: PMID:21625540
        supporting_text: >-
          The J-domain down-regulates the protein level of Atx3 through HSP70 mediated proteasomal
          degradation, while the UIM domain may alleviate this process via maintaining the
          ubiquitinated Atx3.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:24023695
  review:
    summary: >-
      GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962). This IDA
      annotation from Novoselov et al. (2013) is based on data showing that HSJ1a preferentially
      bound to mutant SOD1(G93A) and reduced SOD1 aggregation in a J-domain and UIM-dependent manner.
      The paper describes HSJ1a as acting through a combination of chaperone, co-chaperone, and
      pro-ubiquitylation activity (PMID:24023695). The data demonstrate that DNAJB2 functions as a
      protein folding chaperone that cooperates with HSP70 to actively prevent protein aggregation,
      rather than passively binding unfolded proteins. The replacement term GO:0044183 (protein
      folding chaperone) accurately captures this activity.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. The experimental evidence in Novoselov et al. (2013) shows
      that HSJ1a acts as a chaperone/co-chaperone that cooperates with HSP70 to reduce SOD1
      aggregation via its J domain. The J domain mutant H31Q could still bind mutant SOD1 but
      non-productively, confirming this is active chaperone function rather than passive binding.
      GO:0044183 (protein folding chaperone) is the appropriate replacement.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    additional_reference_ids:
      - PMID:24023695
    supported_by:
      - reference_id: PMID:24023695
        supporting_text: >-
          HSJ1a preferentially bound to mutant SOD1, enhanced SOD1 ubiquitylation and reduced SOD1
          aggregation in a J-domain and ubiquitin interaction motif (UIM) dependent manner.
          Collectively, the data suggest that HSJ1a acts on mutant SOD1 through a combination of
          chaperone, co-chaperone and pro-ubiquitylation activity.
      - reference_id: PMID:24023695
        supporting_text: >-
          The J domain mutant could still bind to mutant SOD1 but the binding appears to be
          non-productive and suggests that HSJ1a co-operates with Hsp70 to actively prevent mutant
          SOD1 aggregation, rather than by a passive chaperone action.
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IDA
  original_reference_id: PMID:7957263
  review:
    summary: >-
      Cheetham et al. (1994) directly demonstrated that HSJ1a and HSJ1b enhance the intrinsic
      ATPase activity of constitutive Hsc70 more than fivefold in vitro (PMID:7957263). This
      enhancement is mediated by an increase in the rate of bound ATP hydrolysis. This is a core
      molecular function of DNAJB2 as a J-domain co-chaperone.
    action: ACCEPT
    reason: >-
      ATPase activator activity is directly demonstrated by in vitro assay showing more than
      fivefold stimulation of Hsc70 ATPase by HSJ1a and HSJ1b (PMID:7957263). This is the
      defining molecular function of J-domain co-chaperones.
    supported_by:
      - reference_id: PMID:7957263
        supporting_text: >-
          The weak intrinsic ATPase activity of the constitutive 70-kDa heat-shock protein
          is enhanced more than fivefold by stoichiometric amounts of both HSJ1a and HSJ1b.
          This enhancement is mediated by an increase in the rate of bound ATP hydrolysis,
          whereas the rate of ADP release is unaffected.
- term:
    id: GO:0032091
    label: negative regulation of protein binding
  evidence_type: IDA
  original_reference_id: PMID:7957263
  review:
    summary: >-
      Cheetham et al. (1994) showed that in the presence of ATP, HSJ1 proteins reduce Hsc70/
      carboxymethylated alpha-lactalbumin complex formation, i.e., they reduce binding of Hsc70
      to its substrate (PMID:7957263). The authors interpreted this as HSJ1 inducing a
      conformational change in Hsc70 that modulates substrate release. This is a mechanistic
      consequence of the J-domain-mediated ATPase cycle regulation, where HSJ1 drives HSP70
      substrate turnover. While the observation is valid, GO:0032091 (negative regulation of
      protein binding) is a very generic biological process term that does not adequately capture
      the specific mechanism.
    action: KEEP_AS_NON_CORE
    reason: >-
      The observation is valid but the term is very general. DNAJB2 modulates Hsc70 substrate
      binding as part of the ATPase cycle, driving substrate release. This is better understood as
      part of the co-chaperone mechanism (regulation of protein folding, ATPase activation) rather
      than as a standalone process. It is a mechanistic detail of the co-chaperone function.
    supported_by:
      - reference_id: PMID:7957263
        supporting_text: >-
          In the presence of ATP, HSJ1 proteins reduce 70-kDa constitutive heat-shock
          protein/carboxymethylated alpha-lactalbumin complex formation both in the presence
          and absence of K+.
- term:
    id: GO:0032781
    label: positive regulation of ATP-dependent activity
  evidence_type: IDA
  original_reference_id: PMID:7957263
  review:
    summary: >-
      Cheetham et al. (1994) showed that HSJ1a and HSJ1b stimulate the ATP-dependent activity
      of Hsc70, enhancing its ATPase activity more than fivefold (PMID:7957263). Positive
      regulation of ATP-dependent activity is an appropriate biological process term that
      captures the downstream effect of the J-domain-mediated ATPase activation.
    action: ACCEPT
    reason: >-
      This accurately describes the biological process resulting from DNAJB2's ATPase activator
      activity. HSJ1 proteins stimulate HSP70 ATP hydrolysis, thereby positively regulating
      ATP-dependent chaperone function (PMID:7957263).
    supported_by:
      - reference_id: PMID:7957263
        supporting_text: >-
          The weak intrinsic ATPase activity of the constitutive 70-kDa heat-shock protein
          is enhanced more than fivefold by stoichiometric amounts of both HSJ1a and HSJ1b.
- term:
    id: GO:1903332
    label: regulation of protein folding
  evidence_type: IDA
  original_reference_id: PMID:7957263
  review:
    summary: >-
      Cheetham et al. (1994) demonstrated that HSJ1 proteins regulate Hsc70 ATPase activity and
      substrate binding, which are the key determinants of chaperone-mediated protein folding
      (PMID:7957263). By modulating the ATPase cycle and substrate release, HSJ1 proteins regulate
      the protein folding activity of Hsc70. This is an appropriate biological process annotation.
    action: ACCEPT
    reason: >-
      Regulation of protein folding accurately captures the biological outcome of DNAJB2's
      co-chaperone activity. By stimulating Hsc70 ATPase and modulating substrate binding, DNAJB2
      regulates the protein folding cycle (PMID:7957263). This is a core biological function.
    supported_by:
      - reference_id: PMID:7957263
        supporting_text: >-
          HSJ1 proteins appear to regulate the affinity of the 70-kDa constitutive heat-shock
          protein for the permanently unfolded substrate, carboxymethylated alpha-lactalbumin.
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IDA
  original_reference_id: PMID:22219199
  review:
    summary: >-
      Gao et al. (2012) confirmed that the J domain of HSJ1a mediates ATPase activation of HSP70,
      using NMR structural studies and in vitro assays (PMID:22219199). They showed the C-terminal
      helical subdomain of HSP70 is crucial for J-domain binding and ATPase stimulation, providing
      the structural basis for this core function.
    action: ACCEPT
    reason: >-
      Independent confirmation of ATPase activator activity using structural and biochemical
      approaches (PMID:22219199). Corroborates the earlier findings of Cheetham et al. (1994).
    supported_by:
      - reference_id: PMID:22219199
        supporting_text: >-
          The C-terminal helical alpha-subdomain of HSP70, which was considered to function as a
          lid of the substrate-binding domain, is crucial for binding with the J domain of HSJ1a
          and stimulating the ATPase activity of HSP70.
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: IPI
  original_reference_id: PMID:22219199
  review:
    summary: >-
      Gao et al. (2012) demonstrated the physical interaction between the J domain of HSJ1a and
      HSP70 using NMR titration and biochemical assays (PMID:22219199). The with/from column
      indicates P0DMV8 (HSPA1A). The paper characterized the structural determinants of this
      interaction, showing the C-terminal helices of HSP70 are essential for J-domain binding.
    action: ACCEPT
    reason: >-
      Direct physical interaction between DNAJB2 J domain and HSP70 is demonstrated by NMR and
      biochemical studies (PMID:22219199). This is a core molecular function.
    supported_by:
      - reference_id: PMID:22219199
        supporting_text: >-
          We studied the interaction between human-inducible HSP70 and Homo sapiens J-domain
          protein (HSJ1a), a J domain and UIM motif-containing co-chaperone.
- term:
    id: GO:0032781
    label: positive regulation of ATP-dependent activity
  evidence_type: IDA
  original_reference_id: PMID:22219199
  review:
    summary: >-
      Gao et al. (2012) confirmed that the J domain of HSJ1a stimulates the ATPase activity of
      HSP70, providing the structural basis for this activation (PMID:22219199). This independent
      confirmation corroborates the earlier functional data from Cheetham et al. (1994).
    action: ACCEPT
    reason: >-
      Independent confirmation of positive regulation of ATP-dependent activity by structural
      and biochemical studies (PMID:22219199).
    supported_by:
      - reference_id: PMID:22219199
        supporting_text: >-
          The C-terminal helical alpha-subdomain of HSP70, which was considered to function as a
          lid of the substrate-binding domain, is crucial for binding with the J domain of HSJ1a
          and stimulating the ATPase activity of HSP70.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      Hageman et al. (2011) observed DNAJB2 in the nucleus by immunofluorescence as part of their
      systematic characterization of HSP70 machine components (PMID:21231916). UniProt confirms
      nuclear localization for isoform 2 (HSJ1a) based on PMID:12754272. The Ottaviani et al. (2017)
      paper also confirmed nuclear and cytosolic localization of HSJ1a in SK-N-SH neuronal cells
      (PMID:28031292).
    action: ACCEPT
    reason: >-
      Nuclear localization is experimentally confirmed by IDA evidence (PMID:21231916) and
      corroborated by multiple studies (PMID:12754272, PMID:28031292). HSJ1a localizes to both
      cytoplasm and nucleus.
    supported_by:
      - reference_id: PMID:28031292
        supporting_text: >-
          In all cases the HSJ1a signal was predominantly in the cytosol and nucleus, as
          previously reported (7).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      Hageman et al. (2011) observed cytosolic localization of DNAJB2 by immunofluorescence as
      part of their systematic HSP70 machine characterization (PMID:21231916). Multiple studies
      confirm that HSJ1a is predominantly cytosolic (PMID:12754272, PMID:28031292).
    action: ACCEPT
    reason: >-
      Cytosol localization is experimentally confirmed by IDA evidence (PMID:21231916) and
      corroborated by multiple studies. HSJ1a is the cytosolic isoform of DNAJB2.
    supported_by:
      - reference_id: PMID:28031292
        supporting_text: >-
          In all cases the HSJ1a signal was predominantly in the cytosol and nucleus, as
          previously reported (7).
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      Hageman et al. (2011) directly assessed protein refolding activity by measuring refolding
      of heat-denatured luciferase upon overexpression of HSP40/DNAJ family members including
      DNAJB2 (PMID:21231916). DNAJB2 showed distinct chaperone-like activities in this systematic
      study. Protein refolding is a core function of the HSP70/HSP40 chaperone machine.
    action: ACCEPT
    reason: >-
      Protein refolding is directly demonstrated by IDA evidence from luciferase refolding assays
      (PMID:21231916). This is a core biological process for DNAJB2 as an HSP70 co-chaperone.
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding genes
          and most of the corresponding proteins are localized in the cytosol. To test for possible
          functional differences and/or substrate specificity, we assessed the effect of
          overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the
          suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin
          fragment.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962). This IDA
      annotation from Hageman et al. (2011) is based on systematic characterization of HSP70 machine
      components. The paper assessed the effect of overexpression of HSP70 and HSP40/DNAJ family
      members on refolding of heat-denatured luciferase and suppression of polyQ aggregation,
      demonstrating that these are protein folding chaperones with distinct chaperone-like activities
      (PMID:21231916). DNAJB2 is part of the HSP70 chaperone machine, functioning as a J-protein
      co-chaperone that assists HSP70 in protein folding. The replacement term GO:0044183 (protein
      folding chaperone) accurately captures this function.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. Hageman et al. (2011) characterized DNAJB2 as part of the
      HSP70 machine with distinct chaperone-like activities including protein refolding and
      aggregation suppression. This is protein folding chaperone activity (GO:0044183), not
      standalone unfolded protein binding. The term GO:0044183 (protein folding chaperone) is the
      appropriate replacement.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    additional_reference_ids:
      - PMID:21231916
      - PMID:24023695
    supported_by:
      - reference_id: PMID:21231916
        supporting_text: >-
          Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding
          genes and most of the corresponding proteins are localized in the cytosol. To
          test for possible functional differences and/or substrate specificity, we
          assessed the effect of overexpression of each of these HSPs on refolding of
          heat-denatured luciferase and on the suppression of aggregation of a
          non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment.
      - reference_id: PMID:24023695
        supporting_text: >-
          The molecular chaperone HSJ1 (DNAJB2) is a member of the Hsp40 (or DnaJ) family of heat
          shock proteins that contain a J domain, which is crucial in substrate recognition by
          Hsp70 [21], [22], [23]. Thus, Hsp40/DnaJ protein function is essential for Hsp70
          function, including protein folding and directing misfolded proteins towards the
          proteasome [23].
- term:
    id: GO:0090084
    label: negative regulation of inclusion body assembly
  evidence_type: IDA
  original_reference_id: PMID:21231916
  review:
    summary: >-
      Hageman et al. (2011) demonstrated that DNAJB2 (and other HSP40/DNAJ family members)
      suppress aggregation of polyQ-expanded Huntingtin fragment, which forms inclusion bodies
      (PMID:21231916). Novoselov et al. (2013) showed HSJ1a reduced SOD1 inclusion formation in
      SK-N-SH cells in a J-domain and UIM-dependent manner (PMID:24023695). Negative regulation of
      inclusion body assembly is a well-characterized function of DNAJB2.
    action: ACCEPT
    reason: >-
      Negative regulation of inclusion body assembly is directly demonstrated by IDA evidence
      showing suppression of polyQ aggregation (PMID:21231916) and SOD1 inclusion formation
      (PMID:24023695). This represents a key biological outcome of DNAJB2's combined chaperone
      and ubiquitin-binding activities.
    supported_by:
      - reference_id: PMID:24023695
        supporting_text: >-
          The expression of HSJ1a led to a significant reduction in SOD1-G93A inclusions and
          redistribution to an even cytoplasmic and nuclear staining pattern similar to the
          SOD1-WT.
- term:
    id: GO:0006986
    label: response to unfolded protein
  evidence_type: TAS
  original_reference_id: PMID:1599432
  review:
    summary: >-
      This TAS annotation from PINC references Cheetham et al. (1992), the original cloning paper
      for HSJ1/DNAJB2 (PMID:1599432). The paper identified HSJ1 as a human DnaJ homologue
      expressed preferentially in neurons, and noted the DnaJ-DnaK interaction is involved in
      protein folding and complex dissociation. The annotation to "response to unfolded protein"
      is appropriate as DNAJB2 is part of the chaperone response to misfolded/unfolded proteins.
      However, DNAJB2 is constitutively expressed and functions as a co-chaperone rather than being
      specifically induced as a stress response. The term is somewhat imprecise for DNAJB2's
      constitutive role.
    action: KEEP_AS_NON_CORE
    reason: >-
      While DNAJB2 is related to DnaJ stress response proteins and functions in protein quality
      control, "response to unfolded protein" implies a stress-responsive process. DNAJB2 is
      constitutively expressed in neurons (PMID:1599432) and functions in basal proteostasis. Its
      core functions are better captured by protein folding, protein refolding, and regulation of
      proteasomal degradation terms. This is not incorrect but is not the most precise description.
    supported_by:
      - reference_id: PMID:1599432
        supporting_text: >-
          The bacterial heat-shock protein DnaJ has been implicated in protein folding and protein
          complex dissociation. The DnaJ protein interacts with the prokaryotic analogue of Hsp70,
          DnaK, and accelerates the rate of ATP hydrolysis by DnaK.
core_functions:
  - molecular_function:
      id: GO:0044183
      label: protein folding chaperone
    description: >-
      DNAJB2 (HSJ1) is a neuronally enriched class B J-domain co-chaperone that functions
      as a "triage" factor in the HSP70-dependent protein quality control pathway. It binds
      misfolded protein substrates and delivers them to HSP70/Hsc70 for refolding or,
      critically, for ubiquitin-dependent proteasomal degradation. The J-domain stimulates
      HSP70 ATPase activity (>5-fold enhancement at stoichiometric amounts, PMID:7957263),
      while two C-terminal UIMs bind polyubiquitin chains and facilitate client delivery
      to the proteasome. DNAJB2 cooperates with CHIP/STUB1 E3 ubiquitin ligase and
      protects polyubiquitin chains from deubiquitylation, supporting a shuttle function
      for ubiquitinated substrates (DOI:10.3390/ijms21041409). CK2 phosphorylation of
      UIM2 (Ser250) modulates ubiquitin-binding capacity (PMID:28031292). DNAJB2
      suppresses aggregation of diverse neurodegeneration-associated substrates (polyQ-
      expanded huntingtin, SOD1, TDP-43, parkin; DOI:10.3389/fncel.2014.00191).
      Mutations cause neuromuscular disease spanning dHMN/CMT2 to neuromyopathy, with
      both recessive and dominant (stop-loss extension) inheritance patterns now
      recognized (DOI:10.1093/hmg/ddad058, DOI:10.1097/WCO.0000000000001299).
    supported_by:
      - reference_id: PMID:24023695
        supporting_text: >-
          The molecular chaperone HSJ1 (DNAJB2) is a member of the Hsp40 (or DnaJ) family of heat
          shock proteins that contain a J domain, which is crucial in substrate recognition by
          Hsp70 [21], [22], [23]. Thus, Hsp40/DnaJ protein function is essential for Hsp70
          function, including protein folding and directing misfolded proteins towards the
          proteasome [23].
      - reference_id: PMID:21231916
        supporting_text: >-
          Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding genes
          and most of the corresponding proteins are localized in the cytosol.
    directly_involved_in:
      - id: GO:0006457
        label: protein folding
      - id: GO:0042026
        label: protein refolding
      - id: GO:0090084
        label: negative regulation of inclusion body assembly
      - id: GO:1903332
        label: regulation of protein folding
      - id: GO:0032781
        label: positive regulation of ATP-dependent activity
    locations:
      - id: GO:0005829
        label: cytosol
      - id: GO:0005634
        label: nucleus
  - molecular_function:
      id: GO:0001671
      label: ATPase activator activity
    description: >-
      DNAJB2 stimulates the intrinsic ATPase activity of HSP70/Hsc70 more than fivefold
      via its J-domain. Both HSJ1a and HSJ1b isoforms enhance ATP hydrolysis by Hsc70,
      driving the chaperone cycle for substrate binding and release.
    supported_by:
      - reference_id: PMID:7957263
        supporting_text: >-
          The weak intrinsic ATPase activity of the constitutive 70-kDa heat-shock protein
          is enhanced more than fivefold by stoichiometric amounts of both HSJ1a and HSJ1b.
          This enhancement is mediated by an increase in the rate of bound ATP hydrolysis,
          whereas the rate of ADP release is unaffected.
      - reference_id: PMID:22219199
        supporting_text: >-
          The C-terminal helical alpha-subdomain of HSP70, which was considered to function as a
          lid of the substrate-binding domain, is crucial for binding with the J domain of HSJ1a
          and stimulating the ATPase activity of HSP70.
    directly_involved_in:
      - id: GO:0032781
        label: positive regulation of ATP-dependent activity
    locations:
      - id: GO:0005829
        label: cytosol
  - molecular_function:
      id: GO:0140036
      label: ubiquitin-modified protein reader activity
    description: >-
      DNAJB2 reads ubiquitin modifications on misfolded client proteins via two C-terminal
      ubiquitin-interacting motifs (UIMs) and facilitates their delivery to the proteasome
      for degradation. It cooperates with the E3 ubiquitin ligase CHIP/STUB1 and protects
      polyubiquitin chains from deubiquitylation, acting as a "neuronal shuttling factor"
      that couples chaperone recognition to proteasomal clearance
      (DOI:10.3390/ijms21041409). CK2 phosphorylation of UIM2 (Ser250) reduces
      ubiquitin-binding capacity, providing a signaling-dependent regulatory switch
      (PMID:28031292). This function distinguishes DNAJB2 from other J-domain proteins
      and is especially critical in long-lived neurons where proteasomal protein
      degradation is essential for proteostasis. The two isoforms (HSJ1a cytosolic/
      nuclear, HSJ1b ER-anchored) operate in distinct compartments to manage both
      cytosolic and ER-associated degradation substrates.
    supported_by:
      - reference_id: PMID:28031292
        supporting_text: >-
          It binds ubiquitylated proteins through its Ubiquitin Interacting Motifs (UIMs) and
          facilitates their delivery to the proteasome for degradation.
      - reference_id: PMID:21625540
        supporting_text: >-
          The J-domain down-regulates the protein level of Atx3 through HSP70 mediated proteasomal
          degradation, while the UIM domain may alleviate this process via maintaining the
          ubiquitinated Atx3.
    directly_involved_in:
      - id: GO:0032436
        label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process
      - id: GO:0031396
        label: regulation of protein ubiquitination
      - id: GO:0090084
        label: negative regulation of inclusion body assembly
    locations:
      - id: GO:0005829
        label: cytosol
      - id: GO:0005634
        label: nucleus
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:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:1599432
  title: Human homologues of the bacterial heat-shock protein DnaJ are preferentially
    expressed in neurons.
  findings: []
- id: PMID:21231916
  title: The diverse members of the mammalian HSP70 machine show distinct chaperone-like
    activities.
  findings: []
- id: PMID:21625540
  title: Co-chaperone HSJ1a dually regulates the proteasomal degradation of ataxin-3.
  findings: []
- id: PMID:22219199
  title: The C-terminal helices of heat shock protein 70 are essential for J-domain
    binding and ATPase activation.
  findings: []
- id: PMID:24023695
  title: Molecular chaperone mediated late-stage neuroprotection in the SOD1(G93A)
    mouse model of amyotrophic lateral sclerosis.
  findings: []
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of
    cellular protein homeostasis pathways.
  findings: []
- id: PMID:28031292
  title: Protein kinase CK2 modulates HSJ1 function through phosphorylation of the
    UIM2 domain.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:7957263
  title: Regulation of 70-kDa heat-shock-protein ATPase activity and substrate binding
    by human DnaJ-like proteins, HSJ1a and HSJ1b.
  findings: []
- id: PMID:9553041
  title: Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires
    association with the inducible chaperone Hsp70.
  findings: []
- id: DOI:10.3390/ijms21041409
  title: Neuromuscular diseases due to chaperone mutations - a review and some new
    results.
  findings:
    - statement: >-
        DNAJB2 cooperates with CHIP/STUB1-mediated ubiquitylation and protects
        polyubiquitin chains from deubiquitylation, supporting a shuttle/stabilization
        role for ubiquitinated clients destined for proteasomal degradation.
    - statement: >-
        CK2 phosphorylation of UIM2 reduces HSJ1's ability to bind ubiquitylated
        clients, providing a kinase-dependent regulatory mechanism for DNAJB2
        proteostasis functions.
- id: DOI:10.1093/hmg/ddad058
  title: Extension of the DNAJB2a isoform in a dominant neuromyopathy family.
  findings:
    - statement: >-
        First dominantly acting DNAJB2 mutation reported: stop-loss variant
        (p.*278Glyext*83) creates a transmembrane helix driving ER mislocalization
        and proteasomal degradation of mutant DNAJB2a with dominant-negative effects
        on wild-type protein.
    - statement: >-
        Approximately 50% reduction of both DNAJB2 isoforms in patient muscle tissue,
        with rapid cycloheximide-chase turnover of the extension mutant rescued by
        MG132 proteasome inhibition.
- id: DOI:10.1097/WCO.0000000000001299
  title: Current advance on distal myopathy genetics.
  findings:
    - statement: >-
        DNAJB2 recognized among newly identified genes for late-onset distal
        myopathy and neuromyopathy, including both recessive and dominant
        inheritance patterns.
- id: DOI:10.3389/fncel.2014.00191
  title: J protein mutations and resulting proteostasis collapse.
  findings:
    - statement: >-
        DNAJB2 is an anti-aggregation cochaperone suppressing aggregation of
        diverse neurodegeneration-associated proteins including polyQ-expanded
        huntingtin, parkin, SOD1, and TDP-43.
- id: DOI:10.3390/neurolint17050073
  title: Impaired DNAJB2 response to heat shock in fibroblasts from a neuropathy
    patient with DNAJB2/HSJ1 mutation - cystamine as a potential therapeutic
    intervention.
  findings:
    - statement: >-
        48-hour pretreatment with cystamine (150 uM) increased DNAJB2 levels in
        both control and patient fibroblasts, supporting a pharmacologic DNAJB2
        boosting strategy.