id: P54811
gene_symbol: cdc-48.1
aliases:
  - C06A1.1
  - p97
  - VCP homolog 1
  - TERA1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: CDC-48.1 is the C. elegans ortholog of mammalian p97/VCP, a highly 
  conserved AAA+ ATPase that functions as a molecular chaperone. It forms 
  homohexameric or heterohexameric rings (with CDC-48.2) and uses ATP hydrolysis
  to generate mechanical force for unfolding substrate proteins, disassembling 
  protein complexes, and disaggregating protein aggregates. CDC-48.1 is 
  essential for ER-associated degradation (ERAD), working with UFD-1/NPL-4 
  adaptors to extract misfolded proteins from the ER for proteasomal 
  degradation. It also functions in DNA replication by promoting degradation of 
  CDT-1 and disassembly of replication complexes, cell cycle progression, 
  chromatin-associated protein degradation, mitotic spindle disassembly, and 
  spermatogenesis regulation. CDC-48.1 works with various UBX domain-containing 
  cofactors (UBXN-1 through UBXN-6) that determine substrate specificity.
existing_annotations:
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: CDC-48.1 localizes to the nucleus where it functions in DNA 
        replication, chromatin-associated degradation, and cell cycle regulation
        (PMID:22735043, PMID:26842564).
      action: ACCEPT
      reason: Nuclear localization is well-supported by phylogenetic inference 
        from orthologs and directly confirmed by experimental evidence in C. 
        elegans showing CDC-48 associates with chromatin and functions in 
        nuclear processes.
      supported_by:
        - reference_id: PMID:22735043
          supporting_text: CDC-48/p97 is a AAA (ATPases associated with diverse 
            cellular activities) chaperone involved in protein conformational 
            changes such as the disassembly of protein complexes
        - reference_id: PMID:26842564
          supporting_text: cellular fractionation of C. elegans embryonic 
            lysates confirmed high abundance of UBXN-3, CDC-48 and CDT-1 in 
            purified nuclei
        - reference_id: file:worm/cdc-48/cdc-48-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0016887
      label: ATP hydrolysis activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ATP hydrolysis activity is the core enzymatic function of 
        CDC-48.1. The protein contains two AAA ATPase domains (D1 and D2) that 
        hydrolyze ATP with positive cooperativity (PMID:21454554, 
        PMID:18782221).
      action: ACCEPT
      reason: This is a core molecular function of CDC-48.1, confirmed by 
        multiple direct biochemical assays showing ATPase activity with defined 
        kinetic parameters.
      supported_by:
        - reference_id: PMID:21454554
          supporting_text: The ATPase activity of the N-terminal AAA domain was 
            very low at physiological temperature, whereas the C-terminal AAA 
            domain showed high ATPase activity in a coordinated fashion with 
            positive cooperativity
        - reference_id: PMID:18782221
          supporting_text: CDC-48.1 and CDC-48.2 suppress the aggregation of a 
            huntingtin (Htt) exon1 fragment containing an expanded polyQ repeat 
            in vitro
  - term:
      id: GO:0051228
      label: mitotic spindle disassembly
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: CDC-48.1 is involved in mitotic spindle disassembly through its 
        role in chromatin decondensation and nuclear envelope re-assembly at the
        end of mitosis.
      action: ACCEPT
      reason: Phylogenetically conserved function supported by IBA from yeast 
        Cdc48 and consistent with C. elegans functional data showing CDC-48 is 
        required for post-mitotic chromatin decondensation.
      supported_by:
        - reference_id: PMID:18728180
          supporting_text: Our analysis of the CDC-48(UFD-1/NPL-4) complex 
            identified a general role in S phase progression of mitotic cells 
            essential for embryonic cell division and germline development of 
            adult worms
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: CDC-48.1 localizes to the cytosol where it functions in ERAD and 
        proteasomal degradation pathways (PMID:16647269, PMID:20977550).
      action: ACCEPT
      reason: Cytosolic localization is phylogenetically conserved and confirmed
        by experimental studies in C. elegans showing CDC-48 functions in 
        cytoplasmic protein degradation pathways.
      supported_by:
        - reference_id: PMID:20977550
          supporting_text: UBXN-1, UBXN-2 and UBXN-3 colocalized with CDC-48 in 
            spermatocytes but not mature sperm
  - term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: CDC-48.1 is a key component of the ubiquitin-proteasome system, 
        binding polyubiquitinated substrates and facilitating their delivery to 
        the proteasome for degradation (PMID:16647269, PMID:21673654).
      action: ACCEPT
      reason: This is a core function of p97/VCP family proteins. CDC-48.1 
        extracts ubiquitinated substrates from complexes and membranes for 
        proteasomal degradation, a function conserved from yeast to humans.
      supported_by:
        - reference_id: PMID:16647269
          supporting_text: the AAA ATPase p97/VCP/CDC48 is required in this 
            pathway for protein dislocation across the ER membrane and 
            subsequent ubiquitin dependent degradation by the 26S proteasome in 
            the cytosol
        - reference_id: PMID:21673654
          supporting_text: EGF signalling alters protein homoeostasis in adults 
            by increasing UPS activity and polyubiquitination, while decreasing 
            protein aggregation
  - term:
      id: GO:0031593
      label: polyubiquitin modification-dependent protein binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: CDC-48.1 binds Lys-48-linked polyubiquitin chains on substrate 
        proteins, enabling their extraction and delivery to the proteasome 
        (PMID:16647269).
      action: ACCEPT
      reason: This is the substrate recognition mechanism for CDC-48/p97 
        proteins. Binding to polyubiquitinated substrates is mediated through 
        adaptor proteins and is essential for ERAD and other degradation 
        pathways.
      supported_by:
        - reference_id: PMID:16647269
          supporting_text: the AAA ATPase p97/VCP/CDC48 is required in this 
            pathway for protein dislocation across the ER membrane and 
            subsequent ubiquitin dependent degradation by the 26S proteasome
  - term:
      id: GO:0030970
      label: retrograde protein transport, ER to cytosol
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: CDC-48.1 is required for retro-translocation of misfolded 
        proteins from the ER lumen to the cytosol for ERAD (PMID:16647269).
      action: ACCEPT
      reason: This is a core function of CDC-48/p97 in ERAD. The protein 
        provides the ATP-dependent force needed to extract substrates through 
        the ER membrane retrotranslocon.
      supported_by:
        - reference_id: PMID:16647269
          supporting_text: these data suggest an evolutionarily conserved 
            retro-translocation machinery at the endoplasmic reticulum
  - term:
      id: GO:0034098
      label: VCP-NPL4-UFD1 AAA ATPase complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: CDC-48.1 forms a complex with UFD-1 and NPL-4 adaptors, the C. 
        elegans equivalent of the mammalian VCP-NPL4-UFD1 complex 
        (PMID:16647269, PMID:20977550).
      action: ACCEPT
      reason: The CDC-48/UFD-1/NPL-4 complex is phylogenetically conserved and 
        has been directly demonstrated in C. elegans through 
        co-immunoprecipitation.
      supported_by:
        - reference_id: PMID:16647269
          supporting_text: both p97 homologs interact with UFD-1/NPL-4 in a 
            similar CDC-48(UFD-1/NPL-4) complex
        - reference_id: PMID:26842564
          supporting_text: UBXN-3 and NPL-4 have been shown to simultaneously 
            bind to single CDC-48 hexamers in vivo
  - term:
      id: GO:0097352
      label: autophagosome maturation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: CDC-48.1 is involved in autophagosome maturation, a 
        phylogenetically conserved function of p97/VCP proteins.
      action: ACCEPT
      reason: p97/VCP is known to function in autophagy in mammals and other 
        organisms. The IBA annotation reflects this conserved function.
  - term:
      id: GO:0000166
      label: nucleotide binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: CDC-48.1 contains two AAA ATPase domains that bind ATP. This 
        general term is captured by the more specific ATP binding annotation.
      action: ACCEPT
      reason: Nucleotide binding is an accurate but general descriptor. CDC-48.1
        binds ATP through its two AAA domains. While redundant with more 
        specific terms, this IEA annotation is not incorrect.
  - term:
      id: GO:0005524
      label: ATP binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: CDC-48.1 binds ATP through its two AAA ATPase domains (D1 and 
        D2). ATP binding to D1 induces conformational changes that regulate D2 
        ATPase activity (PMID:21454554, PMID:24055316).
      action: ACCEPT
      reason: ATP binding is essential for CDC-48.1 function and is inferred 
        correctly from InterPro domain annotations (AAA ATPase domains).
      supported_by:
        - reference_id: PMID:21454554
          supporting_text: p97 is composed of two conserved AAA (ATPases 
            associated with diverse cellular activities) domains, which form a 
            tandem hexameric ring
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: Nuclear localization is inferred by machine learning and 
        confirmed experimentally (PMID:22735043, PMID:18728180).
      action: ACCEPT
      reason: This is a duplicate of the IBA annotation but with IEA evidence. 
        Both are correct as CDC-48.1 localizes to both cytoplasm and nucleus.
      supported_by:
        - reference_id: PMID:22735043
          supporting_text: CDC-48/p97 is required for proper meiotic chromosome 
            segregation via controlling AIR-2/Aurora B kinase localization in 
            Caenorhabditis elegans
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: CDC-48.1 is present in the cytoplasm where it functions in ERAD 
        and proteasomal degradation (PMID:16647269, PMID:20977550).
      action: ACCEPT
      reason: Cytoplasmic localization is correctly inferred from UniProt 
        subcellular location data and confirmed by experimental studies.
      supported_by:
        - reference_id: PMID:20977550
          supporting_text: UBXN-1, UBXN-2 and UBXN-3 colocalized with CDC-48 in 
            spermatocytes but not mature sperm
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: CDC-48.1 associates with the ER membrane during ERAD to extract 
        misfolded proteins for degradation (PMID:16647269).
      action: ACCEPT
      reason: ER membrane association is consistent with CDC-48.1's role in 
        retro-translocation during ERAD.
      supported_by:
        - reference_id: PMID:16647269
          supporting_text: the AAA ATPase p97/VCP/CDC48 is required in this 
            pathway for protein dislocation across the ER membrane
  - term:
      id: GO:0009792
      label: embryo development ending in birth or egg hatching
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: CDC-48.1 is essential for embryonic development in C. elegans. 
        RNAi knockdown causes embryonic lethality, especially when combined with
        cdc-48.2 depletion (PMID:16647269, PMID:18728180).
      action: KEEP_AS_NON_CORE
      reason: While CDC-48.1 is required for embryonic development, this is a 
        pleiotropic phenotype resulting from its core functions in ERAD, DNA 
        replication, and cell cycle control rather than a primary developmental 
        function.
      supported_by:
        - reference_id: PMID:16647269
          supporting_text: RNAi mediated depletion of the corresponding genes 
            induces ER stress resulting in hypersensitivity to conditions which 
            induce increased levels of unfolded proteins in the ER lumen
        - reference_id: PMID:18728180
          supporting_text: These developmental defects result from activation of
            the DNA replication checkpoint caused by replication stress
  - term:
      id: GO:0010498
      label: proteasomal protein catabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: CDC-48.1 facilitates proteasomal degradation by extracting 
        ubiquitinated substrates and delivering them to the proteasome.
      action: ACCEPT
      reason: This is a core function of CDC-48.1, closely related to its role 
        in ERAD and ubiquitin-dependent protein degradation.
      supported_by:
        - reference_id: PMID:16647269
          supporting_text: subsequent ubiquitin dependent degradation by the 26S
            proteasome in the cytosol
  - term:
      id: GO:0016787
      label: hydrolase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: CDC-48.1 has ATP hydrolase (ATPase) activity through its AAA 
        domains. This general term is subsumed by the more specific ATP 
        hydrolysis activity.
      action: ACCEPT
      reason: Hydrolase activity is correctly inferred from domain annotations. 
        While redundant with ATP hydrolysis activity, it is not incorrect.
  - term:
      id: GO:0016887
      label: ATP hydrolysis activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: ATP hydrolysis activity is inferred from AAA ATPase domain 
        annotations and confirmed by direct enzymatic assays (PMID:21454554).
      action: ACCEPT
      reason: Correctly inferred core function, also supported by IDA and IBA 
        evidence.
      supported_by:
        - reference_id: PMID:21454554
          supporting_text: We characterized the ATP hydrolysis mechanism of 
            CDC-48.1, a p97 homolog of Caenorhabditis elegans
  - term:
      id: GO:0017111
      label: ribonucleoside triphosphate phosphatase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: This term is a parent of ATP hydrolysis activity. CDC-48.1 
        specifically hydrolyzes ATP, not other NTPs.
      action: MODIFY
      reason: While technically correct as a parent term of ATP hydrolysis 
        activity, this annotation is too general. CDC-48.1 is an ATPase; there 
        is no evidence it has significant activity on other ribonucleoside 
        triphosphates.
      proposed_replacement_terms:
        - id: GO:0016887
          label: ATP hydrolysis activity
  - term:
      id: GO:0032880
      label: regulation of protein localization
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: CDC-48.1 regulates protein localization, particularly 
        chromatin-associated proteins like CDT-1 and AIR-2 (PMID:26842564, 
        PMID:22735043).
      action: ACCEPT
      reason: CDC-48.1 regulates the localization of multiple substrates through
        its segregase activity, extracting proteins from complexes and promoting
        their degradation or relocalization.
      supported_by:
        - reference_id: PMID:26842564
          supporting_text: UBXN-3/FAF1 binds to the licensing factor CDT-1 and 
            additional ubiquitylated proteins, thus promoting 
            CDC-48/p97-dependent turnover and disassembly of DNA replication 
            factor complexes
  - term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: CDC-48.1 is essential for the response to ER stress through its 
        role in ERAD. Depletion causes accumulation of misfolded proteins and 
        induction of the unfolded protein response (PMID:16647269).
      action: ACCEPT
      reason: CDC-48.1 is a key component of the ERAD pathway that resolves ER 
        stress by eliminating misfolded proteins.
      supported_by:
        - reference_id: PMID:16647269
          supporting_text: RNAi mediated depletion of the corresponding genes 
            induces ER stress resulting in hypersensitivity to conditions which 
            induce increased levels of unfolded proteins in the ER lumen
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: CDC-48.1 forms homohexamers through self-association 
        (PMID:18782221, PMID:24055316).
      action: ACCEPT
      reason: Homohexamer formation is essential for CDC-48.1 function and has 
        been directly demonstrated biochemically.
      supported_by:
        - reference_id: PMID:24055316
          supporting_text: p97 (also called VCP and CDC-48) is an AAA+ 
            chaperone, which consists of a substrate/cofactor-binding N domain 
            and two ATPase domains (D1 and D2), and forms a homo-hexameric ring
        - reference_id: PMID:21454554
          supporting_text: p97 is composed of two conserved AAA (ATPases 
            associated with diverse cellular activities) domains, which form a 
            tandem hexameric ring
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: CDC-48.1 localizes to the perinuclear region in spermatocytes 
        (PMID:20977550).
      action: ACCEPT
      reason: Perinuclear localization has been directly observed by 
        immunofluorescence.
      supported_by:
        - reference_id: PMID:20977550
          supporting_text: UBXN-1, UBXN-2 and UBXN-3 colocalized with CDC-48 in 
            spermatocytes but not mature sperm
  - term:
      id: GO:0098796
      label: membrane protein complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: This term suggests CDC-48.1 is part of a membrane protein 
        complex, which is not its primary form of association.
      action: MARK_AS_OVER_ANNOTATED
      reason: While CDC-48.1 associates with the ER membrane during ERAD, it is 
        primarily a soluble cytoplasmic/nuclear protein that transiently 
        associates with membranes. The VCP-NPL4-UFD1 complex is the appropriate 
        complex annotation. This annotation is misleading.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14704431
    review:
      summary: Protein binding detected in high-throughput Y2H interactome 
        mapping study.
      action: MARK_AS_OVER_ANNOTATED
      reason: '"Protein binding" is too general and uninformative. CDC-48.1 has specific
        binding partners including UBX domain proteins, UFD-1, NPL-4, and substrates.
        High-throughput Y2H provides limited mechanistic insight.'
      supported_by:
        - reference_id: PMID:14704431
          supporting_text: more than 4000 interactions were identified from 
            high-throughput, yeast two-hybrid (HT=Y2H) screens
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19123269
    review:
      summary: Protein binding with CDC-48.2 (P54812) detected in Y2H 
        interactome mapping.
      action: MARK_AS_OVER_ANNOTATED
      reason: General protein binding is uninformative. The interaction with 
        CDC-48.2 reflects heterohexamer formation, but this is better captured 
        by the identical protein binding annotation.
      supported_by:
        - reference_id: PMID:19123269
          supporting_text: "We present an expanded Caenorhabditis elegans protein-protein
            interaction network, or \"interactome\" map derived from testing a matrix
            of ~ 10,000 × ~ 10,000 proteins using a highly specific high-throughput
            yeast two-hybrid system"
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:24055316
    review:
      summary: High-speed atomic force microscopy study demonstrating CDC-48.1 
        homohexamer formation and ATP-dependent conformational changes.
      action: ACCEPT
      reason: This study provides direct structural evidence for CDC-48.1 
        self-association into hexameric rings, a core property of the protein.
      supported_by:
        - reference_id: PMID:24055316
          supporting_text: we studied the conformational changes of hexameric 
            CDC-48.1, a Caenorhabditis elegans p97 homolog, using high-speed 
            atomic force microscopy
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25721663
    review:
      summary: Study characterizing CDC-48 interaction with UFD-2 and UFD-3 
        C-terminal adaptors in regulation of polyglutamine aggregation.
      action: MODIFY
      reason: The study provides specific information about binding to UFD-3 
        adaptor. A more specific term would be informative.
      proposed_replacement_terms:
        - id: GO:0044877
          label: protein-containing complex binding
      supported_by:
        - reference_id: PMID:25721663
          supporting_text: CDC-48 preferentially interacts with UFD-3 in 
            Caenorhabditis elegans
  - term:
      id: GO:0032436
      label: positive regulation of proteasomal ubiquitin-dependent protein 
        catabolic process
    evidence_type: IMP
    original_reference_id: PMID:21673654
    review:
      summary: CDC-48.1 promotes proteasomal degradation as part of the EGF 
        signaling pathway that modulates lifespan through increased UPS 
        activity.
      action: ACCEPT
      reason: This captures CDC-48.1's role in facilitating proteasomal 
        degradation, demonstrated by mutant phenotype analysis.
      supported_by:
        - reference_id: PMID:21673654
          supporting_text: EGF signalling alters protein homoeostasis in adults 
            by increasing UPS activity and polyubiquitination, while decreasing 
            protein aggregation
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20977550
    review:
      summary: Study demonstrating CDC-48 interactions with multiple UBX 
        cofactors (UBXN-1 through UBXN-6) and their role in spermatogenesis.
      action: MODIFY
      reason: This reflects specific binding to UBX domain adaptor proteins. 
        More specific annotation would be preferable.
      proposed_replacement_terms:
        - id: GO:0044877
          label: protein-containing complex binding
      supported_by:
        - reference_id: PMID:20977550
          supporting_text: All six UBXN proteins directly interacted with 
            CDC-48.1 and CDC-48.2
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23649807
    review:
      summary: Study showing UBXN-2 interaction with CDC-48 regulates Aurora A 
        at centrosomes during mitosis.
      action: MODIFY
      reason: This reflects specific binding to UBXN-2 adaptor protein in the 
        context of centrosome regulation.
      proposed_replacement_terms:
        - id: GO:0044877
          label: protein-containing complex binding
      supported_by:
        - reference_id: PMID:23649807
          supporting_text: UBXN-2 and CDC-48 limit AIR-1 accumulation at 
            centrosomes in prophase
  - term:
      id: GO:0034098
      label: VCP-NPL4-UFD1 AAA ATPase complex
    evidence_type: IDA
    original_reference_id: PMID:20977550
    review:
      summary: Direct evidence for CDC-48.1 forming a complex with UFD-1 and 
        NPL-4 adaptors in C. elegans.
      action: ACCEPT
      reason: This is well-supported by co-immunoprecipitation and functional 
        studies showing the CDC-48/UFD-1/NPL-4 complex is essential for multiple
        cellular processes.
      supported_by:
        - reference_id: PMID:26842564
          supporting_text: UBXN-3 and NPL-4 have been shown to simultaneously 
            bind to single CDC-48 hexamers in vivo
  - term:
      id: GO:0044877
      label: protein-containing complex binding
    evidence_type: IDA
    original_reference_id: PMID:20977550
    review:
      summary: CDC-48.1 binds to protein complexes containing UBXN adaptors and 
        substrates for extraction and processing.
      action: ACCEPT
      reason: CDC-48.1's segregase function involves binding to and 
        disassembling protein complexes, which is the molecular basis for this 
        annotation.
      supported_by:
        - reference_id: PMID:20977550
          supporting_text: these results suggest that UBXN-1, UBXN-2 and UBXN-3 
            are redundant cofactors for CDC-48/p97 and control spermatogenesis 
            via the degradation of TRA-1A
  - term:
      id: GO:0045977
      label: positive regulation of mitotic cell cycle, embryonic
    evidence_type: IGI
    original_reference_id: PMID:26842564
    review:
      summary: CDC-48.1 promotes embryonic cell cycle progression through its 
        role in DNA replication and degradation of replication factors.
      action: ACCEPT
      reason: The study demonstrates that CDC-48/UBXN-3 function is required for
        proper S phase progression and cell cycle timing.
      supported_by:
        - reference_id: PMID:26842564
          supporting_text: progression of the DNA replication fork is 
            coordinated by UBXN-3/FAF1. UBXN-3/FAF1 binds to the licensing 
            factor CDT-1 and additional ubiquitylated proteins, thus promoting 
            CDC-48/p97-dependent turnover and disassembly of DNA replication 
            factor complexes
  - term:
      id: GO:1905634
      label: regulation of protein localization to chromatin
    evidence_type: IGI
    original_reference_id: PMID:26842564
    review:
      summary: CDC-48.1 regulates the chromatin association of DNA replication 
        factors including CDT-1 and CDC-45/GINS complex components.
      action: ACCEPT
      reason: The study directly demonstrates CDC-48 regulates chromatin 
        association of multiple replication factors.
      supported_by:
        - reference_id: PMID:26842564
          supporting_text: inactivation of UBXN-3/FAF1 stabilizes CDT-1 and 
            CDC-45/GINS on chromatin, causing severe defects in replication fork
            dynamics
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:22735043
    review:
      summary: Direct observation of CDC-48 localization in the nucleus during 
        meiosis and mitosis in C. elegans.
      action: ACCEPT
      reason: Nuclear localization directly demonstrated by fluorescence 
        microscopy.
      supported_by:
        - reference_id: PMID:22735043
          supporting_text: CDC-48/p97 is required for proper meiotic chromosome 
            segregation via controlling AIR-2/Aurora B kinase localization
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: PMID:22735043
    review:
      summary: CDC-48 localizes to the nucleoplasm where it regulates meiotic 
        chromosome segregation.
      action: ACCEPT
      reason: Nucleoplasmic localization is consistent with CDC-48's role in 
        regulating chromatin-associated proteins during cell division.
      supported_by:
        - reference_id: PMID:22735043
          supporting_text: CDC-48s control the restricted localization of AIR-2 
            to the cohesion sites of homologous chromatids in meiosis I
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:22735043
    review:
      summary: CDC-48 is present in the cytoplasm as shown by immunofluorescence
        studies.
      action: ACCEPT
      reason: Cytoplasmic localization directly observed.
      supported_by:
        - reference_id: PMID:22735043
          supporting_text: CDC-48/p97 is a AAA (ATPases associated with diverse 
            cellular activities) chaperone involved in protein conformational 
            changes such as the disassembly of protein complexes
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:20977550
    review:
      summary: CDC-48 localizes to the perinuclear region in spermatocytes.
      action: ACCEPT
      reason: Perinuclear localization directly demonstrated by 
        immunofluorescence.
      supported_by:
        - reference_id: PMID:20977550
          supporting_text: UBXN-1, UBXN-2 and UBXN-3 colocalized with CDC-48 in 
            spermatocytes but not mature sperm
  - term:
      id: GO:0016887
      label: ATP hydrolysis activity
    evidence_type: IDA
    original_reference_id: PMID:18854144
    review:
      summary: This reference studies CDC-48.3, a distinct Afg2/Spaf subfamily 
        member, not CDC-48.1. However, ATP hydrolysis activity for CDC-48.1 is 
        well-established by other references (PMID:21454554, PMID:18782221).
      action: ACCEPT
      reason: Although PMID:18854144 specifically studies CDC-48.3 (not 
        CDC-48.1), the annotation of ATP hydrolysis activity is correct for 
        CDC-48.1 based on other direct enzymatic assays (see PMID:21454554).
      supported_by:
        - reference_id: PMID:18854144
          supporting_text: This screen uncovered a member of the Afg2/Spaf 
            subfamily of Cdc48-like AAA ATPases as an essential inhibitor of 
            AIR-2 stability and activity
  - term:
      id: GO:0016887
      label: ATP hydrolysis activity
    evidence_type: IDA
    original_reference_id: PMID:18782221
    review:
      summary: Biochemical characterization of CDC-48.1 ATPase activity in the 
        context of polyQ aggregate suppression.
      action: ACCEPT
      reason: Direct enzymatic assay demonstrating ATPase activity.
      supported_by:
        - reference_id: PMID:18782221
          supporting_text: CDC-48.1 and CDC-48.2 suppress the aggregation of a 
            huntingtin (Htt) exon1 fragment containing an expanded polyQ repeat 
            in vitro
  - term:
      id: GO:0016887
      label: ATP hydrolysis activity
    evidence_type: IDA
    original_reference_id: PMID:21454554
    review:
      summary: Detailed biochemical characterization of CDC-48.1 ATPase 
        mechanism showing positive cooperativity between the two AAA domains.
      action: ACCEPT
      reason: Comprehensive enzymatic analysis with kinetic parameters and 
        mutagenesis defining the catalytic mechanism.
      supported_by:
        - reference_id: PMID:21454554
          supporting_text: The ATPase activity of the N-terminal AAA domain was 
            very low at physiological temperature, whereas the C-terminal AAA 
            domain showed high ATPase activity in a coordinated fashion with 
            positive cooperativity
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:18728180
    review:
      summary: Nuclear localization of CDC-48 demonstrated in the context of DNA
        replication and cell cycle studies.
      action: ACCEPT
      reason: Nuclear localization directly observed, consistent with CDC-48's 
        role in DNA replication control.
      supported_by:
        - reference_id: PMID:18728180
          supporting_text: Our analysis of the CDC-48(UFD-1/NPL-4) complex 
            identified a general role in S phase progression of mitotic cells 
            essential for embryonic cell division and germline development of 
            adult worms
  - term:
      id: GO:0009792
      label: embryo development ending in birth or egg hatching
    evidence_type: IGI
    original_reference_id: PMID:16647269
    review:
      summary: CDC-48.1 is required for embryonic development, with combined 
        cdc-48.1/cdc-48.2 depletion causing embryonic lethality.
      action: KEEP_AS_NON_CORE
      reason: Embryonic lethality is a pleiotropic phenotype reflecting CDC-48's
        essential roles in ERAD, cell cycle, and proteostasis rather than a 
        specific developmental function.
      supported_by:
        - reference_id: PMID:16647269
          supporting_text: RNAi mediated depletion of the corresponding genes 
            induces ER stress resulting in hypersensitivity to conditions which 
            induce increased levels of unfolded proteins in the ER lumen
  - term:
      id: GO:0034098
      label: VCP-NPL4-UFD1 AAA ATPase complex
    evidence_type: IPI
    original_reference_id: PMID:16647269
    review:
      summary: Physical interaction between CDC-48 and UFD-1 demonstrated, 
        establishing the C. elegans CDC-48/UFD-1/NPL-4 complex.
      action: ACCEPT
      reason: Direct physical interaction evidence for complex formation.
      supported_by:
        - reference_id: PMID:16647269
          supporting_text: both p97 homologs interact with UFD-1/NPL-4 in a 
            similar CDC-48(UFD-1/NPL-4) complex
  - term:
      id: GO:0036503
      label: ERAD pathway
    evidence_type: IGI
    original_reference_id: PMID:16647269
    review:
      summary: CDC-48.1 is a core component of the ERAD pathway in C. elegans, 
        required for degradation of misfolded ER proteins.
      action: ACCEPT
      reason: ERAD is a primary, well-established function of CDC-48/p97 
        proteins across eukaryotes. Direct genetic evidence supports this in C. 
        elegans.
      supported_by:
        - reference_id: PMID:16647269
          supporting_text: these data suggest an evolutionarily conserved 
            retro-translocation machinery at the endoplasmic reticulum
references:
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    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:14704431
    title: A map of the interactome network of the metazoan C. elegans.
    findings: []
  - id: PMID:16647269
    title: A conserved role of Caenorhabditis elegans CDC-48 in ER-associated 
      protein degradation.
    findings:
      - statement: CDC-48.1 and CDC-48.2 interact with UFD-1/NPL-4 to form the 
          conserved CDC-48(UFD-1/NPL-4) complex
        supporting_text: both p97 homologs interact with UFD-1/NPL-4 in a 
          similar CDC-48(UFD-1/NPL-4) complex
      - statement: RNAi depletion induces ER stress and sensitivity to unfolded 
          protein accumulation
        supporting_text: RNAi mediated depletion of the corresponding genes 
          induces ER stress resulting in hypersensitivity to conditions which 
          induce increased levels of unfolded proteins in the ER lumen
      - statement: Demonstrates evolutionarily conserved retro-translocation 
          machinery at the ER
        supporting_text: these data suggest an evolutionarily conserved 
          retro-translocation machinery at the endoplasmic reticulum
  - id: PMID:18728180
    title: Cell cycle progression requires the CDC-48UFD-1/NPL-4 complex for 
      efficient DNA replication.
    findings:
      - statement: CDC-48(UFD-1/NPL-4) complex is required for S phase 
          progression
        supporting_text: Our analysis of the CDC-48(UFD-1/NPL-4) complex 
          identified a general role in S phase progression of mitotic cells 
          essential for embryonic cell division and germline development of 
          adult worms
      - statement: Developmental defects result from DNA replication checkpoint 
          activation
        supporting_text: These developmental defects result from activation of 
          the DNA replication checkpoint caused by replication stress
      - statement: CDC-48 depletion causes reduced DNA content and decreased DNA
          synthesis
        supporting_text: DNA content is strongly reduced in worms depleted for 
          CDC-48, UFD-1, and NPL-4. In addition, these worms show decreased DNA 
          synthesis
  - id: PMID:18782221
    title: p97 Homologs from Caenorhabditis elegans, CDC-48.1 and CDC-48.2, 
      suppress the aggregate formation of huntingtin exon1 containing expanded 
      polyQ repeat.
    findings:
      - statement: CDC-48.1 and CDC-48.2 directly bind huntingtin exon1 fragment
        supporting_text: CDC-48.1 and CDC-48.2 bound the Htt exon1 fragment 
          directly
      - statement: Suppress SDS-insoluble aggregate formation independently of 
          nucleotides
        supporting_text: suppressed the formation of SDS-insoluble aggregates of
          Htt fragments containing 53 glutamine residues (HttQ53) independently 
          of nucleotides
      - statement: Modulate oligomeric states during aggregate formation 
          suggesting chaperone function
        supporting_text: CDC-48.1 and CDC-48.2 also modulated the oligomeric 
          states of HttQ53 during the aggregate formation
  - id: PMID:18854144
    title: An Afg2/Spaf-related Cdc48-like AAA ATPase regulates the stability 
      and activity of the C. elegans Aurora B kinase AIR-2.
    findings: []
  - id: PMID:19123269
    title: Empirically controlled mapping of the Caenorhabditis elegans 
      protein-protein interactome network.
    findings: []
  - id: PMID:20977550
    title: Caenorhabditis elegans UBX cofactors for CDC-48/p97 control 
      spermatogenesis.
    findings:
      - statement: All six UBXN proteins (UBXN-1 to UBXN-6) directly interact 
          with CDC-48.1
        supporting_text: All six UBXN proteins directly interacted with CDC-48.1
          and CDC-48.2
      - statement: UBXN-1, UBXN-2, UBXN-3 colocalize with CDC-48 in 
          spermatocytes
        supporting_text: UBXN-1, UBXN-2 and UBXN-3 colocalized with CDC-48 in 
          spermatocytes but not mature sperm
      - statement: UBX cofactors control spermatogenesis via TRA-1A degradation
        supporting_text: these results suggest that UBXN-1, UBXN-2 and UBXN-3 
          are redundant cofactors for CDC-48/p97 and control spermatogenesis via
          the degradation of TRA-1A
  - id: PMID:21454554
    title: Positive cooperativity of the p97 AAA ATPase is critical for 
      essential functions.
    findings:
      - statement: N-terminal AAA domain has low ATPase activity
        supporting_text: The ATPase activity of the N-terminal AAA domain was 
          very low at physiological temperature
      - statement: C-terminal AAA domain shows high ATPase activity with 
          positive cooperativity
        supporting_text: the C-terminal AAA domain showed high ATPase activity 
          in a coordinated fashion with positive cooperativity
      - statement: Positive cooperativity is critical for essential functions
        supporting_text: the positive cooperativity is critical for the 
          essential functions of p97
  - id: PMID:21673654
    title: EGF signalling activates the ubiquitin proteasome system to modulate 
      C. elegans lifespan.
    findings:
      - statement: EGF signaling upregulates UPS genes including CDC-48 pathway 
          components
        supporting_text: EGF signalling upregulates the expression of genes 
          involved in the ubiquitin proteasome system (UPS)
      - statement: UFD complex required for increased UPS activity in adults
        supporting_text: SKR-5 and the E3/E4 ligases that comprise the ubiquitin
          fusion degradation (UFD) complex are required for the increase in UPS 
          activity observed in adults
      - statement: UPS activity regulates protein homeostasis and lifespan
        supporting_text: EGF signalling alters protein homoeostasis in adults by
          increasing UPS activity and polyubiquitination, while decreasing 
          protein aggregation
  - id: PMID:22735043
    title: CDC-48/p97 is required for proper meiotic chromosome segregation via 
      controlling AIR-2/Aurora B kinase localization in Caenorhabditis elegans.
    findings:
      - statement: CDC-48s required for proper chromosome segregation during 
          meiosis
        supporting_text: CDC-48s are required for proper chromosome segregation 
          during meiosis in C. elegans
      - statement: Controls restricted localization of AIR-2 to cohesion sites 
          of homologous chromatids
        supporting_text: CDC-48s control the restricted localization of AIR-2 to
          the cohesion sites of homologous chromatids in meiosis I
      - statement: Depletion causes expansion of AIR-2 signals over entire 
          length of meiotic chromosomes
        supporting_text: depletion of CDC-48s resulted in a significant 
          expansion of signals for AIR-2 and phosphorylated histone H3 over the 
          entire length of meiotic chromosomes
  - id: PMID:23649807
    title: The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by 
      limiting the centrosomal recruitment of Aurora A.
    findings:
      - statement: UBXN-2 interacts with CDC-48 to regulate centrosome 
          maturation timing
        supporting_text: UBXN-2 and CDC-48 limit AIR-1 accumulation at 
          centrosomes in prophase
  - id: PMID:24055316
    title: High-speed atomic force microscopic observation of ATP-dependent 
      rotation of the AAA+ chaperone p97.
    findings:
      - statement: CDC-48.1 forms hexameric ring
        supporting_text: p97 (also called VCP and CDC-48) is an AAA+ chaperone, 
          which consists of a substrate/cofactor-binding N domain and two ATPase
          domains (D1 and D2), and forms a homo-hexameric ring
      - statement: ATP binding induces rotation of N-D1 ring relative to D2 ring
        supporting_text: "In the presence of ATP, the N-D1 ring repeatedly rotates
          ~23 ± 8° clockwise and resets relative to the D2 ring"
      - statement: Rotation induced by ATP binding to D2 domain
        supporting_text: Mutational analysis reveals that this rotation is 
          induced by ATP binding to the D2 domain
  - id: PMID:25721663
    title: Characterization of C-terminal adaptors, UFD-2 and UFD-3, of CDC-48 
      on the polyglutamine aggregation in C. elegans.
    findings:
      - statement: CDC-48 preferentially interacts with UFD-3 in C. elegans
        supporting_text: CDC-48 preferentially interacts with UFD-3 in 
          Caenorhabditis elegans
  - id: PMID:26842564
    title: Chromatin-associated degradation is defined by UBXN-3/FAF1 to 
      safeguard DNA replication fork progression.
    findings:
      - statement: UBXN-3/FAF1 binds CDT-1 and ubiquitylated proteins to promote
          CDC-48-dependent turnover
        supporting_text: UBXN-3/FAF1 binds to the licensing factor CDT-1 and 
          additional ubiquitylated proteins, thus promoting CDC-48/p97-dependent
          turnover and disassembly of DNA replication factor complexes
      - statement: CDC-48 and UBXN-3 associate with chromatin in nuclei
        supporting_text: cellular fractionation of C. elegans embryonic lysates 
          confirmed high abundance of UBXN-3, CDC-48 and CDT-1 in purified 
          nuclei
      - statement: Regulates disassembly of DNA replication factor complexes
        supporting_text: promoting CDC-48/p97-dependent turnover and disassembly
          of DNA replication factor complexes
      - statement: Controls progression of DNA replication fork
        supporting_text: progression of the DNA replication fork is coordinated 
          by UBXN-3/FAF1
  - id: file:worm/cdc-48/cdc-48-deep-research-falcon.md
    title: Deep research report on cdc-48.1
    findings: []
core_functions:
  - molecular_function:
      id: GO:0016887
      label: ATP hydrolysis activity
    description: Core enzymatic function enabling all CDC-48.1 activities. The 
      protein uses ATP hydrolysis to generate mechanical force for substrate 
      unfolding and complex disassembly.
  - molecular_function:
      id: GO:0031593
      label: polyubiquitin modification-dependent protein binding
    directly_involved_in:
      - id: GO:0036503
        label: ERAD pathway
    description: CDC-48.1 is essential for retro-translocation of misfolded 
      proteins from the ER to the cytosol for proteasomal degradation, 
      preventing ER stress and UPR activation.
  - molecular_function:
      id: GO:0016887
      label: ATP hydrolysis activity
    directly_involved_in:
      - id: GO:0043161
        label: proteasome-mediated ubiquitin-dependent protein catabolic process
    in_complex:
      id: GO:0034098
      label: VCP-NPL4-UFD1 AAA ATPase complex
    description: CDC-48.1 extracts polyubiquitinated substrates from complexes 
      and membranes and delivers them to the proteasome for degradation.
  - molecular_function:
      id: GO:0016887
      label: ATP hydrolysis activity
    directly_involved_in:
      - id: GO:0051228
        label: mitotic spindle disassembly
    locations:
      - id: GO:0005634
        label: nucleus
    description: CDC-48.1 functions in post-mitotic processes including 
      chromatin decondensation and nuclear envelope reassembly.
  - molecular_function:
      id: GO:0016887
      label: ATP hydrolysis activity
    directly_involved_in:
      - id: GO:1905634
        label: regulation of protein localization to chromatin
    locations:
      - id: GO:0005654
        label: nucleoplasm
    description: CDC-48.1 regulates chromatin association of DNA replication 
      factors, controlling replication fork progression and cell cycle timing.
proposed_new_terms: []
suggested_questions:
  - question: What is the specific mechanism by which CDC-48.1 extracts AIR-2 
      from chromatin during meiosis?
  - question: How do different UBX domain adaptors determine CDC-48.1 substrate 
      specificity?
  - question: What is the relationship between CDC-48.1 and CDC-48.2 in terms of
      functional redundancy and hetero-oligomer formation?
suggested_experiments:
  - description: Determine crystal structure of CDC-48.1 with different UBX 
      adaptors to understand substrate selection
  - description: Identify the complete set of CDC-48.1 substrates using 
      proximity labeling approaches
  - description: Test whether CDC-48.1 chaperone activity (ATP-independent) 
      contributes to polyQ suppression in vivo
tags:
  - caeel-proteostasis