nud-1

id: G5EE74
gene_symbol: nud-1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: >-
  C. elegans NUD-1 (Nuclear migration protein nudC) is an evolutionarily conserved
  member of the NudC family that functions in nuclear migration, mitotic progression,
  and cytoskeletal dynamics. NUD-1 associates with microtubules and the dynein motor
  complex, working alongside LIS-1 to ensure proper cell division and nuclear positioning
  (PMID:11685578). The protein contains a conserved p23/HSP20-like domain (CS domain)
  and an N-terminal NudC domain. In vitro studies demonstrate that NUD-1 exhibits
  ATP-independent molecular chaperone (holdase) activity, preventing aggregation of
  citrate synthase and luciferase at stoichiometric concentrations, and protecting
  native enzyme activity from thermal inactivation (PMID:18626791). Importantly,
  NUD-1/substrate complexes are productive -- unfolded intermediates can be refolded
  by ATP-dependent chaperones, indicating NUD-1 acts as a holdase that maintains
  substrates in a refolding-competent state (PMID:18626791). NUD-1 is expressed in
  sensory neurons, embryos, gonad, gut, vulva, ventral cord, and hypodermal seam
  cells (PMID:11685578). RNAi knockdown causes embryonic lethality, sterility,
  altered vulval morphology, uncoordinated movement, and nuclear positioning defects
  in early embryonic cell division (PMID:11685578). Depletion of NUD-1 also leads to
  defective GABA synaptic vesicle trafficking and increased susceptibility to
  pentylenetetrazole-induced convulsions (PMID:16996038).
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for cytoplasmic localization, inferred phylogenetically from
      multiple orthologs including Drosophila, Arabidopsis, and human NudC proteins.
      Consistent with UniProt subcellular location annotation (Cytoplasm) and the
      known biology of NudC family proteins as cytoplasmic, microtubule-associated
      proteins. NUD-1::GFP fusion shows cytoplasmic expression in sensory neurons,
      embryos, gonad, gut, vulva, ventral cord, and hypodermal seam cells (PMID:11685578).
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is well-established for NUD-1 and the NudC family.
      The IBA inference is consistent with UniProt annotation and direct GFP expression
      data in C. elegans (PMID:11685578).
    supported_by:
      - reference_id: PMID:11685578
        supporting_text: >-
          A C. elegans nud-1::GFP fusion produces sustained fluorescence in sensory
          neurons and embryos, and transient fluorescence in the gonad, gut, vulva,
          ventral cord, and hypodermal seam cells.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for involvement in protein folding, inferred phylogenetically.
      NUD-1 has been demonstrated to exhibit chaperone activity in vitro
      (PMID:18626791), preventing aggregation of citrate synthase and luciferase.
      However, NUD-1 functions as a holdase rather than a foldase -- it prevents
      aggregation of unfolded substrates, which can then be refolded by ATP-dependent
      chaperones. The IBA annotation is consistent with the experimental evidence
      from PMID:18626791.
    action: ACCEPT
    reason: >-
      Protein folding is appropriate as a biological process annotation for a holdase
      chaperone, as NUD-1 maintains unfolded intermediates in a refolding-competent
      state that can be subsequently refolded by the cellular chaperone machinery
      (PMID:18626791). The IBA inference is supported by direct experimental evidence.
    supported_by:
      - reference_id: PMID:18626791
        supporting_text: >-
          In the presence of NUD-1, nearly all of the luciferase activity was regained,
          indicating that unfolded intermediates complexed with NUD-1 could be refolded.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for unfolded protein binding, inferred phylogenetically from
      NUD-1 itself (WB:WBGene00003829) and other orthologs. GO:0051082 is proposed
      for obsoletion. NUD-1 has been directly demonstrated to prevent aggregation of
      denaturing citrate synthase and luciferase (PMID:18626791), functioning as
      an ATP-independent holdase chaperone. However, NUD-1 is not a classical sHSP --
      it is a NudC family protein with an HSP20-like fold (CS domain) whose primary
      role is in nuclear migration and cytoskeletal dynamics. The chaperone activity
      may be secondary to its role in mitotic complex assembly.
    action: MODIFY
    reason: >-
      GO:0051082 is proposed for obsoletion. NUD-1 demonstrates holdase activity in
      vitro (PMID:18626791), preventing aggregation of denaturing substrates and
      maintaining them in a refolding-competent state. GO:0140309 (unfolded protein
      carrier activity) is not appropriate because it is carrier-specific (per
      go-ontology#30552). Retain until a holdase chaperone activity NTR is created.
    proposed_replacement_terms:
      - id: GO:0051082
        label: unfolded protein binding (retain until holdase NTR is created)
    supported_by:
      - reference_id: PMID:18626791
        supporting_text: >-
          We demonstrate that nematode NUD-1 is able to prevent the aggregation of two
          substrate proteins, citrate synthase (CS) and luciferase, at stoichiometric
          concentrations.
- term:
    id: GO:0045202
    label: synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: >-
      IEA annotation for synaptic localization, inferred automatically from
      the GO:0051932 (synaptic transmission, GABAergic) annotation via
      inter-ontology logical inference. NUD-1 depletion causes defective GABA
      synaptic vesicle trafficking (PMID:16996038), which supports a role at
      synapses. However, this is an indirect inference -- NUD-1 may affect
      synaptic vesicle trafficking through its role in cytoskeletal dynamics
      (dynein/microtubule-dependent transport) rather than being a resident
      synaptic protein.
    action: KEEP_AS_NON_CORE
    reason: >-
      The inference from GABAergic synaptic transmission to synaptic localization
      is logically valid. NUD-1 depletion disrupts GABA synaptic vesicle
      trafficking (PMID:16996038), suggesting functional involvement at synapses.
      However, NUD-1 is primarily a cytoplasmic, microtubule-associated protein
      and its synaptic role is secondary to its core function in nuclear migration
      and chaperone activity.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for cytoplasmic localization based on UniProt subcellular
      location mapping. Consistent with the IBA annotation for the same term and
      direct GFP expression data (PMID:11685578).
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is well-established. This IEA annotation is consistent
      with the IBA annotation and experimental evidence. Acceptable as automated
      confirmation.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:18626791
  review:
    summary: >-
      IDA annotation for involvement in protein folding based on Faircloth et al. 2009
      (PMID:18626791). The study demonstrated that recombinant NUD-1 prevents
      aggregation of citrate synthase and luciferase, protects native CS from thermal
      inactivation, and maintains unfolded luciferase intermediates in a
      refolding-competent state. This is directly supported by the luciferase refolding
      assay showing that unfolded intermediates complexed with NUD-1 could be refolded
      by rabbit reticulocyte lysate plus ATP.
    action: ACCEPT
    reason: >-
      Strong experimental evidence directly in C. elegans NUD-1 demonstrating
      chaperone activity that facilitates the protein folding process. NUD-1 acts as a
      holdase maintaining substrates in a refolding-competent state, which is part of
      the protein folding pathway (PMID:18626791).
    supported_by:
      - reference_id: PMID:18626791
        supporting_text: >-
          In the presence of NUD-1, nearly all of the luciferase activity was regained,
          indicating that unfolded intermediates complexed with NUD-1 could be refolded.
      - reference_id: PMID:18626791
        supporting_text: >-
          NUD-1 also protects the native state of CS from thermal inactivation by
          significantly reducing the inactivation rate of this enzyme.
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IDA
  original_reference_id: PMID:18626791
  review:
    summary: >-
      IDA annotation for protein folding chaperone molecular function based on
      Faircloth et al. 2009 (PMID:18626791). The study directly demonstrated that
      NUD-1 possesses ATP-independent chaperone activity comparable to small heat
      shock proteins and cochaperones. NUD-1 prevents aggregation of denaturing
      citrate synthase and luciferase at stoichiometric concentrations, and maintains
      substrates in a refolding-competent state. This is a more informative molecular
      function annotation than GO:0051082 (unfolded protein binding), as it captures
      the active chaperone function.
    action: ACCEPT
    reason: >-
      GO:0044183 (protein folding chaperone) accurately describes the molecular
      function of NUD-1 as demonstrated by in vitro chaperone assays (PMID:18626791).
      The term captures the holdase activity, including prevention of aggregation and
      maintenance of refolding-competent intermediates. This is a well-supported
      core molecular function annotation.
    supported_by:
      - reference_id: PMID:18626791
        supporting_text: >-
          NUD-1 possesses ATP-independent chaperone activity comparable to that of small
          heat shock proteins and cochaperones and that changes in phosphorylation state
          functionally alter chaperone activity in a phosphomimetic NUD-1 mutant.
      - reference_id: PMID:18626791
        supporting_text: >-
          We demonstrate that nematode NUD-1 is able to prevent the aggregation of two
          substrate proteins, citrate synthase (CS) and luciferase, at stoichiometric
          concentrations.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:18626791
  review:
    summary: >-
      IDA annotation for unfolded protein binding based on Faircloth et al. 2009
      (PMID:18626791). The study demonstrated that NUD-1 binds denaturing proteins
      (citrate synthase and luciferase) and prevents their aggregation. GO:0051082
      is proposed for obsoletion. The more informative annotation GO:0044183
      (protein folding chaperone) is already annotated with IDA evidence from the
      same publication, and GO:0140309 (unfolded protein carrier activity) would
      be the recommended replacement for the holdase function.
    action: MODIFY
    reason: >-
      GO:0051082 is proposed for obsoletion. The holdase activity demonstrated in
      PMID:18626791 is not well captured by GO:0140309 (carrier-specific, per
      go-ontology#30552). GO:0044183 (protein folding chaperone) is already
      annotated from the same evidence. Retain until a holdase chaperone activity
      NTR is created.
    proposed_replacement_terms:
      - id: GO:0051082
        label: unfolded protein binding (retain until holdase NTR is created)
    supported_by:
      - reference_id: PMID:18626791
        supporting_text: >-
          We demonstrate that nematode NUD-1 is able to prevent the aggregation of two
          substrate proteins, citrate synthase (CS) and luciferase, at stoichiometric
          concentrations.
- term:
    id: GO:0048489
    label: synaptic vesicle transport
  evidence_type: IMP
  original_reference_id: PMID:16996038
  review:
    summary: >-
      IMP annotation for involvement in synaptic vesicle transport based on Locke
      et al. 2006 (PMID:16996038). The study used fluorescent markers for synaptic
      vesicle trafficking and found that depletion of NUD-1 (along with other LIS1
      pathway components) resulted in defective GABA synaptic vesicle trafficking.
      This is consistent with NUD-1's role in dynein-dependent transport along
      microtubules.
    action: KEEP_AS_NON_CORE
    reason: >-
      The experimental evidence from PMID:16996038 supports involvement in synaptic
      vesicle transport, likely through NUD-1's role in the dynein motor complex and
      microtubule-based transport. However, this is a secondary consequence of NUD-1's
      core function in cytoskeletal dynamics rather than a specialized role in synaptic
      vesicle trafficking per se. Retained as non-core.
    supported_by:
      - reference_id: PMID:16996038
        supporting_text: >-
          We found that depletion of LIS1 pathway components resulted in defective GABA
          synaptic vesicle trafficking.
- term:
    id: GO:0051932
    label: synaptic transmission, GABAergic
  evidence_type: IGI
  original_reference_id: PMID:16996038
  review:
    summary: >-
      IGI annotation for involvement in GABAergic synaptic transmission based on
      Locke et al. 2006 (PMID:16996038). The study used genetic interaction
      experiments with LIS-1 pathway components (indicated by with/from
      WB:WBGene00003047) and pentylenetetrazole exposure to demonstrate that NUD-1
      depletion affects GABAergic neurotransmission, resulting in convulsion
      susceptibility.
    action: KEEP_AS_NON_CORE
    reason: >-
      The genetic interaction evidence supports a role in GABAergic synaptic
      transmission, likely secondary to NUD-1's role in microtubule-dependent
      transport of synaptic vesicles. This is a non-core function reflecting the
      downstream effects of disrupted cytoskeletal dynamics on neuronal function.
    supported_by:
      - reference_id: PMID:16996038
        supporting_text: >-
          Worms depleted for LIS1 pathway components (NUD-1, NUD-2, DHC-1, CDK-5,
          and CDKA-1) exhibited significant convulsions following PTZ and RNAi
          treatment.
- term:
    id: GO:0040011
    label: locomotion
  evidence_type: IMP
  original_reference_id: PMID:11685578
  review:
    summary: >-
      IMP annotation for involvement in locomotion based on Dawe et al. 2001
      (PMID:11685578). RNAi knockdown of nud-1 resulted in uncoordinated movement,
      one of several pleiotropic phenotypes observed. This is a downstream consequence
      of NUD-1's role in neuronal development and function rather than a direct role
      in locomotion.
    action: KEEP_AS_NON_CORE
    reason: >-
      The uncoordinated movement phenotype from nud-1 RNAi (PMID:11685578) is a
      pleiotropic effect of disrupting this broadly required nuclear migration/
      cytoskeletal dynamics gene, not a specific role in locomotion. Retained as
      non-core.
    supported_by:
      - reference_id: PMID:11685578
        supporting_text: >-
          Phenotypic analysis of either nud-1 and lis-1 by RNA interference yielded
          similar phenotypes, including embryonic lethality, sterility, altered vulval
          morphology, and uncoordinated movement.
- term:
    id: GO:0040025
    label: vulval development
  evidence_type: IMP
  original_reference_id: PMID:11685578
  review:
    summary: >-
      IMP annotation for involvement in vulval development based on Dawe et al. 2001
      (PMID:11685578). RNAi knockdown of nud-1 resulted in altered vulval morphology.
      nud-1::GFP shows expression in the vulva, and vulval development requires
      proper cell division and nuclear migration, consistent with NUD-1's core
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Altered vulval morphology from nud-1 RNAi (PMID:11685578) is a pleiotropic
      phenotype consistent with disruption of nuclear migration and cell division
      in vulval precursor cells. nud-1::GFP is expressed in the vulva. Retained as
      non-core since vulval development is not the primary function of NUD-1.
    supported_by:
      - reference_id: PMID:11685578
        supporting_text: >-
          Phenotypic analysis of either nud-1 and lis-1 by RNA interference yielded
          similar phenotypes, including embryonic lethality, sterility, altered vulval
          morphology, and uncoordinated movement.
- term:
    id: GO:0009792
    label: embryo development ending in birth or egg hatching
  evidence_type: IMP
  original_reference_id: PMID:11685578
  review:
    summary: >-
      IMP annotation for involvement in embryo development based on Dawe et al. 2001
      (PMID:11685578). RNAi knockdown of nud-1 caused embryonic lethality and nuclear
      positioning defects in early embryonic cell division similar to dynein/dynactin
      depletion. This is a core biological process for NUD-1 given its essential role
      in nuclear migration during cell division.
    action: ACCEPT
    reason: >-
      Embryonic lethality from nud-1 RNAi represents a core phenotype (PMID:11685578).
      NUD-1 is essential for proper nuclear positioning during early embryonic cell
      division, and its requirement for embryo development is a direct consequence of
      its core function in nuclear migration and mitotic progression.
    supported_by:
      - reference_id: PMID:11685578
        supporting_text: >-
          Digital time-lapse video microscopy was used to determine that RNAi-treated
          embryos exhibited nuclear positioning defects in early embryonic cell division
          similar to those reported for dynein/dynactin depletion.
- term:
    id: GO:0035046
    label: pronuclear migration
  evidence_type: IMP
  original_reference_id: PMID:11685578
  review:
    summary: >-
      IMP annotation for involvement in pronuclear migration based on Dawe et al.
      2001 (PMID:11685578). RNAi knockdown of nud-1 caused nuclear positioning
      defects in early embryonic cell division. Pronuclear migration is a
      dynein-dependent process, and NUD-1 functions with the dynein motor complex.
      This is a core biological process directly reflecting NUD-1's primary
      molecular role in nuclear migration.
    action: ACCEPT
    reason: >-
      Pronuclear migration is a core function of NUD-1, directly reflecting its
      primary role in nuclear migration via the dynein motor complex. The nuclear
      positioning defects observed after nud-1 RNAi (PMID:11685578) are consistent
      with the conserved role of NudC family proteins in nuclear migration from
      fungi to humans. The gene name itself (nuclear distribution) reflects this
      function.
    supported_by:
      - reference_id: PMID:11685578
        supporting_text: >-
          Digital time-lapse video microscopy was used to determine that RNAi-treated
          embryos exhibited nuclear positioning defects in early embryonic cell division
          similar to those reported for dynein/dynactin depletion.
      - reference_id: PMID:11685578
        supporting_text: >-
          Heterologous expression of the C. elegans nudC ortholog, nud-1, complements
          the A. nidulans nudC3 mutant, demonstrating evolutionary conservation of
          function.
- term:
    id: GO:0051932
    label: synaptic transmission, GABAergic
  evidence_type: IMP
  original_reference_id: PMID:16996038
  review:
    summary: >-
      IMP annotation for involvement in GABAergic synaptic transmission based on
      Locke et al. 2006 (PMID:16996038). NUD-1-depleted worms exhibited significant
      convulsions following PTZ treatment, and fluorescent markers showed defective
      GABA synaptic vesicle trafficking. This is a separate evidence line (IMP vs IGI)
      from the other GO:0051932 annotation for the same gene from the same paper.
    action: KEEP_AS_NON_CORE
    reason: >-
      This IMP annotation provides independent evidence from the IGI annotation for
      the same term. The convulsion susceptibility phenotype after NUD-1 depletion
      (PMID:16996038) supports involvement in GABAergic signaling, but this is a
      secondary function stemming from NUD-1's role in microtubule-based transport.
      Retained as non-core.
    supported_by:
      - reference_id: PMID:16996038
        supporting_text: >-
          Worms depleted for LIS1 pathway components (NUD-1, NUD-2, DHC-1, CDK-5,
          and CDKA-1) exhibited significant convulsions following PTZ and RNAi
          treatment.
references:
- 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:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: PMID:11685578
  title: Evolutionarily conserved nuclear migration genes required for early embryonic
    development in Caenorhabditis elegans.
  findings:
    - statement: >-
        RNAi knockdown of nud-1 causes embryonic lethality, sterility, altered vulval
        morphology, uncoordinated movement, and nuclear positioning defects in early
        embryonic cell division similar to dynein/dynactin depletion.
      supporting_text: >-
        Phenotypic analysis of either nud-1 and lis-1 by RNA interference yielded
        similar phenotypes, including embryonic lethality, sterility, altered vulval
        morphology, and uncoordinated movement.
- id: PMID:16996038
  title: Genetic interactions among cortical malformation genes that influence susceptibility
    to convulsions in C. elegans.
  findings:
    - statement: >-
        Depletion of NUD-1 and other LIS1 pathway components caused defective GABA
        synaptic vesicle trafficking and significant convulsions following
        pentylenetetrazole treatment.
      supporting_text: >-
        Worms depleted for LIS1 pathway components (NUD-1, NUD-2, DHC-1, CDK-5,
        and CDKA-1) exhibited significant convulsions following PTZ and RNAi
        treatment.
- id: PMID:18626791
  title: The microtubule-associated protein, NUD-1, exhibits chaperone activity in
    vitro.
  findings:
    - statement: >-
        Recombinant C. elegans NUD-1 prevents aggregation of citrate synthase and
        luciferase at stoichiometric concentrations, protects native CS from thermal
        inactivation, and maintains unfolded intermediates in a refolding-competent
        state. NUD-1 possesses ATP-independent chaperone activity comparable to
        small heat shock proteins.
      supporting_text: >-
        We demonstrate that nematode NUD-1 is able to prevent the aggregation of two
        substrate proteins, citrate synthase (CS) and luciferase, at stoichiometric
        concentrations.
core_functions:
  - molecular_function:
      id: GO:0044183
      label: protein folding chaperone
    directly_involved_in:
      - id: GO:0006457
        label: protein folding
      - id: GO:0035046
        label: pronuclear migration
      - id: GO:0009792
        label: embryo development ending in birth or egg hatching
    locations:
      - id: GO:0005737
        label: cytoplasm
    description: >-
      NUD-1 functions as an ATP-independent holdase chaperone that prevents
      aggregation of denaturing proteins and maintains substrates in a
      refolding-competent state (PMID:18626791). This chaperone activity,
      mediated by its conserved p23/HSP20-like CS domain, likely supports
      its essential role in nuclear migration and mitotic progression by
      maintaining the integrity of key protein complexes (dynein, LIS-1)
      required for cell division. NUD-1 is required for proper pronuclear
      migration and embryo development (PMID:11685578).