abu-1

id: Q17400
gene_symbol: abu-1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: ABU-1 (Activated in Blocked Unfolded protein response) is a type I transmembrane
  protein that functions in an alternative ER stress response pathway. Unlike canonical
  UPR genes that are induced by the IRE1-XBP-1 pathway, abu-1 is specifically upregulated
  when this canonical pathway is blocked. ABU-1 localizes to the ER membrane and intracellular
  vesicular structures. The protein contains a signal sequence, a lumenal domain with
  similarity to scavenger receptors, a transmembrane domain, and a short cytoplasmic
  tail. ABU-1 is essential for survival of animals with a blocked UPR under ER stress
  conditions, suggesting it provides a backup mechanism for handling misfolded ER
  client proteins. The lumenal domain shares similarity with mammalian scavenger receptors
  and C. elegans CED-1, suggesting ABU-1 may bind to altered ER client proteins and
  modulate their intracellular fate.
existing_annotations:
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ABU-1 localization to ER membrane is well-supported by experimental data.
      In C. elegans, ABU-1-GFP localizes to vesicular structures within the endomembrane
      system (PMID:12186849). When expressed in mammalian COS-1 cells, FLAG-tagged
      ABU-1 shows a diffuse reticular pattern that colocalizes with the ER marker
      ribophorin I. The protein is retained in the ER by its transmembrane domain.
    action: ACCEPT
    reason: The IBA annotation is consistent with direct experimental evidence from
      PMID:12186849 showing ABU-1 colocalization with ER marker ribophorin I in mammalian
      cells and association with the endomembrane system in C. elegans. The IDA annotation
      from the same publication provides experimental validation.
    supported_by:
    - reference_id: PMID:12186849
      supporting_text: "Immunostaining of the FLAG-tagged ABU-1\u2013expressing COS1\
        \ cells with anti-FLAG antibodies showed a diffuse reticular pattern that\
        \ colocalized with the ER marker ribophorin I"
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: The IBA annotation for ER UPR involvement is appropriate but requires
      careful interpretation. ABU-1 is part of an ALTERNATIVE pathway that is activated
      when the canonical IRE1-XBP-1 UPR pathway is blocked. It is not induced by ER
      stress in wild-type animals but specifically in xbp-1 mutants (PMID:12186849).
      The GO term captures the general involvement in ER stress response, though the
      mechanism is distinct from canonical UPR.
    action: ACCEPT
    reason: While ABU-1 functions in an alternative rather than canonical UPR pathway,
      the GO term GO:0030968 (endoplasmic reticulum unfolded protein response) is
      appropriately broad to encompass this function. The term definition includes
      responses to unfolded proteins in the ER, which ABU-1 participates in, albeit
      through a non-canonical mechanism. RNAi knockdown of abu-1 causes ER stress
      and kills ER-stressed animals with blocked UPR, demonstrating its role in maintaining
      ER homeostasis.
    supported_by:
    - reference_id: PMID:12186849
      supporting_text: Nine of these encode highly similar, novel proteins with a
        hydrophobic NH2-terminal signal sequence, a potential transmembrane domain,
        and a short COOH-terminal cytoplasmic domain
    - reference_id: PMID:12186849
      supporting_text: These observations are consistent with a role for abu-1 (and
        possibly other ABU genes) in protecting animals with a defective UPR against
        ER stress
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: HEP
  original_reference_id: PMID:12186849
  review:
    summary: The HEP (high-throughput expression pattern) annotation is based on microarray
      expression data from PMID:12186849 showing that abu-1 is induced by ER stress
      (tunicamycin treatment) specifically in xbp-1 mutant animals. Northern blot
      analysis confirmed this expression pattern.
    action: ACCEPT
    reason: The expression pattern evidence correctly captures that abu-1 is transcriptionally
      induced during ER stress conditions, specifically in animals with blocked canonical
      UPR. This is valid evidence for involvement in ER stress response processes.
    supported_by:
    - reference_id: PMID:12186849
      supporting_text: Northern blot analysis confirmed the induction of abu-1 by
        tunicamycin treatment of xbp-1 mutant animals but not wild-type animals
    - reference_id: PMID:12186849
      supporting_text: We refer to members of this family as activated in blocked
        UPR (abu)
- term:
    id: GO:0003674
    label: molecular_function
  evidence_type: ND
  original_reference_id: GO_REF:0000015
  review:
    summary: The ND (No biological Data) annotation indicates that no specific molecular
      function has been experimentally determined for ABU-1. While the protein has
      sequence similarity to scavenger receptors and may bind to altered ER client
      proteins, this has not been directly demonstrated.
    action: ACCEPT
    reason: This is an appropriate use of ND. Although PMID:12186849 suggests that
      ABU proteins may bind to altered ER client proteins based on sequence similarity
      to scavenger receptors, no direct biochemical demonstration of a specific molecular
      function has been published. The authors state this is a hypothesis.
    supported_by:
    - reference_id: PMID:12186849
      supporting_text: It is possible therefore that the ABU proteins may be playing
        a similar role within the endomembrane system, perhaps by binding to altered
        ER client proteins and modulating their intracellular fate
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:12186849
  review:
    summary: Direct experimental evidence from PMID:12186849 demonstrates ABU-1 localization
      to the ER membrane. When expressed in mammalian COS-1 cells, FLAG-tagged ABU-1
      shows colocalization with the ER marker ribophorin I. In C. elegans, ABU-1-GFP
      localizes to vesicular structures within the endomembrane system. The protein
      is retained in the ER by its transmembrane domain, as deletion of this domain
      leads to secretion.
    action: ACCEPT
    reason: 'The IDA annotation is well-supported by multiple lines of experimental
      evidence from PMID:12186849: (1) colocalization with ER marker ribophorin I
      in mammalian cells, (2) localization to intracellular vesicular structures in
      C. elegans, (3) membrane retention is dependent on the transmembrane domain.
      This is a core localization for understanding ABU-1 function.'
    supported_by:
    - reference_id: PMID:12186849
      supporting_text: "Immunostaining of the FLAG-tagged ABU-1\u2013expressing COS1\
        \ cells with anti-FLAG antibodies showed a diffuse reticular pattern that\
        \ colocalized with the ER marker ribophorin I"
    - reference_id: PMID:12186849
      supporting_text: "The fluorescence pattern of ABU-1\u2013GFP suggested that\
        \ the protein was associated with the intracellular endomembrane system"
    - reference_id: PMID:12186849
      supporting_text: Deletion of the predicted transmembrane domain led to secretion
        of the protein into the culture media
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IMP
  original_reference_id: PMID:12186849
  review:
    summary: 'The IMP (Inferred from Mutant Phenotype) annotation is supported by
      RNAi knockdown experiments in PMID:12186849. Inactivation of abu-1 by RNAi:
      (1) activated the ER stress marker hsp-4::gfp in otherwise normal animals, indicating
      development of ER stress; (2) killed approximately 50% of ER-stressed ire-1
      and xbp-1 mutant animals; (3) had synthetic interactions with sel-1 (ERAD component).
      These phenotypes demonstrate a functional role in ER stress response.'
    action: ACCEPT
    reason: The IMP evidence from RNAi experiments clearly demonstrates that abu-1
      functions in ER homeostasis. Loss of function causes ER stress (hsp-4::gfp activation)
      and is lethal in combination with canonical UPR mutants under stress conditions.
      This is strong genetic evidence for involvement in ER stress response pathways.
    supported_by:
    - reference_id: PMID:12186849
      supporting_text: RNA-mediated interference (RNAi) inactivation of a representative
        abu family member, abu-1 (AC3.3), activated the ER stress marker hsp-4::gfp
        in otherwise normal animals and killed 50% of ER-stressed ire-1 and xbp-1
        mutant animals
    - reference_id: PMID:12186849
      supporting_text: abu-1(RNAi) upregulated the ER stress reporter gene hsp-4::gfp
        in the intestine
    - reference_id: PMID:12186849
      supporting_text: These observations suggest that abu-1 (and possibly other abu
        genes) and sel-1 perform partially redundant functions in animals with a blocked
        UPR
references:
- id: GO_REF:0000015
  title: Use of the ND evidence code for Gene Ontology (GO) terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: PMID:12186849
  title: A survival pathway for Caenorhabditis elegans with a blocked unfolded protein
    response.
  findings:
  - statement: ABU-1 is part of a novel gene family (abu genes) specifically induced
      when the canonical IRE1-XBP-1 UPR pathway is blocked.
    supporting_text: We refer to members of this family as activated in blocked UPR
      (abu)
  - statement: Nine abu genes encode highly related type I transmembrane proteins
      with similarity to mammalian scavenger receptors.
    supporting_text: Nine of these encode highly similar, novel proteins with a hydrophobic
      NH2-terminal signal sequence, a potential transmembrane domain, and a short
      COOH-terminal cytoplasmic domain
  - statement: ABU-1 localizes to the ER membrane and intracellular vesicular structures.
    supporting_text: "Immunostaining of the FLAG-tagged ABU-1\u2013expressing COS1\
      \ cells with anti-FLAG antibodies showed a diffuse reticular pattern that colocalized\
      \ with the ER marker ribophorin I"
  - statement: RNAi knockdown of abu-1 causes ER stress and is lethal for ER-stressed
      animals with blocked canonical UPR.
    supporting_text: RNA-mediated interference (RNAi) inactivation of a representative
      abu family member, abu-1 (AC3.3), activated the ER stress marker hsp-4::gfp
      in otherwise normal animals and killed 50% of ER-stressed ire-1 and xbp-1 mutant
      animals
  - statement: ABU-1 may function by binding altered ER client proteins and modulating
      their intracellular fate, similar to scavenger receptors.
    supporting_text: It is possible therefore that the ABU proteins may be playing
      a similar role within the endomembrane system, perhaps by binding to altered
      ER client proteins and modulating their intracellular fate
  - statement: abu-1 genetically interacts with sel-1 (ERAD component), suggesting
      parallel or overlapping functions in protein quality control.
    supporting_text: These observations suggest that abu-1 (and possibly other abu
      genes) and sel-1 perform partially redundant functions in animals with a blocked
      UPR
core_functions:
- molecular_function:
    id: GO:0003674
    label: molecular_function
  description: The specific molecular function of ABU-1 remains unknown. Based on
    sequence similarity to scavenger receptors and CED-1, ABU-1 may function as a
    receptor for misfolded or modified proteins within the ER lumen, but this has
    not been experimentally demonstrated.
  directly_involved_in:
  - id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
suggested_questions:
- question: What is the direct molecular function of ABU-1? Does it act as a receptor
    for misfolded proteins in the ER lumen?
- question: How is abu-1 transcriptionally regulated in xbp-1 mutants? Is it dependent
    on PERK/PEK-1 or ATF6/ATF-6?
- question: Do all nine ABU family members have redundant functions, or do they have
    specialized roles?
- question: What is the significance of the constitutive expression of abu-1 in the
    pharynx?
- question: Does ABU-1 directly interact with ERAD components or function in a parallel
    pathway?
suggested_experiments:
- description: Biochemical identification of ABU-1 binding partners in the ER lumen
    to determine if it directly binds misfolded proteins.
- description: Structure-function analysis of the scavenger receptor-like domain to
    identify residues required for function.
- description: Single and combinatorial knockouts of all abu family members to determine
    redundancy and synthetic genetic interactions.
- description: Identification of the transcription factor(s) responsible for abu-1
    induction in xbp-1 mutants.
- description: Proteomics analysis to identify proteins that accumulate when abu-1
    is inactivated.
proposed_new_terms: []
tags:
- caeel-upr-stress