id: Q8NC44
gene_symbol: RETREG2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  RETREG2 (reticulophagy regulator 2; also called FAM134A) is an
  endoplasmic-reticulum (ER) membrane protein of the FAM134/RETREG family
  (RETREG1/FAM134B, RETREG2/FAM134A, RETREG3/FAM134C) that functions as a
  selective-autophagy receptor for the ER (ER-phagy/reticulophagy). It is a
  multi-pass ER membrane protein whose transmembrane segments form a
  reticulon-homology domain (RHD) that bends and shapes ER membranes, and it
  carries a cytosolic LC3-interacting region (LIR) motif that binds ATG8-family
  proteins (LC3/GABARAP). RETREG2 is held in an inactive state under basal
  conditions and is activated by cellular stress; once activated it promotes ER
  fragmentation and delivers ER fragments into lysosomes by sequestering them
  into autophagosomes through its LIR-mediated interaction with ATG8 proteins,
  thereby driving selective turnover of the ER. Beyond bulk ER-phagy, the FAM134
  paralogues contribute to ER membrane remodeling and to collagen quality
  control (the latter reported to be LIR-independent). RETREG2 localizes to the
  ER membrane.
existing_annotations:
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference of membrane localization; correct but a generic parent of the specific ER membrane localization.
    action: KEEP_AS_NON_CORE
    reason: Correct but overly generic; the specific endoplasmic reticulum membrane annotation captures RETREG2's actual localization.
    supported_by:
    - reference_id: file:human/RETREG2/RETREG2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of ER membrane localization from UniProt; the correct core compartment, redundant with experimental EXP evidence.
    action: ACCEPT
    reason: Core localization; RETREG2 is a multi-pass ER membrane protein that acts as an ER-phagy receptor.
    supported_by:
    - reference_id: file:human/RETREG2/RETREG2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:34338405}'
- term:
    id: GO:0061753
    label: substrate localization to autophagosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: Inter-ontology logical inference of substrate localization to autophagosome; consistent with RETREG2 delivering ER fragments into autophagosomes.
    action: ACCEPT
    reason: Core process; RETREG2 sequesters ER substrate into autophagosomes via its LIR-ATG8 interaction during ER-phagy.
    supported_by:
    - reference_id: file:human/RETREG2/RETREG2-uniprot.txt
      supporting_text: mediates ER delivery into lysosomes through sequestration into autophagosomes via interaction with ATG8 family proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21900206
  qualifier: enables
  review:
    summary: High-throughput directed protein-interaction-network interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26040720
  qualifier: enables
  review:
    summary: Interaction(s) from the foundational ER-phagy/FAM134 selective-autophagy study (e.g. ATG8/LC3 family). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records functionally relevant ER-phagy interactions but the bare term is uninformative; the ER-autophagosome adaptor activity annotation captures the function.
    supported_by:
    - reference_id: PMID:26040720
      supporting_text: Regulation of endoplasmic reticulum turnover by selective autophagy
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of endoplasmic reticulum localization; correct but a generic parent of the specific ER membrane localization.
    action: KEEP_AS_NON_CORE
    reason: Correct but overly generic; the specific ER membrane annotation captures RETREG2's localization as a multi-pass ER membrane protein.
    supported_by:
    - reference_id: file:human/RETREG2/RETREG2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0140506
    label: endoplasmic reticulum-autophagosome adaptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-transferred (Ensembl Compara) ER-autophagosome adaptor activity; the precise molecular function of RETREG2 as an ER-phagy receptor that bridges the ER membrane to ATG8/autophagosomes via its LIR motif.
    action: ACCEPT
    reason: Core molecular function; RETREG2 is an ER-phagy receptor whose LIR motif tethers the ER to autophagosomes (ATG8 family), exactly captured by this term.
    supported_by:
    - reference_id: file:human/RETREG2/RETREG2-uniprot.txt
      supporting_text: 'DOMAIN: The LIR motif interacts with ATG8 family proteins'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:34338405
  qualifier: located_in
  review:
    summary: Experimental evidence (FAM134 paralogue study) for ER membrane localization of RETREG2/FAM134A. Core compartment.
    action: ACCEPT
    reason: Direct experimental support for the core ER membrane localization where RETREG2 functions in ER-phagy.
    supported_by:
    - reference_id: PMID:34338405
      supporting_text: Role of FAM134 paralogues in endoplasmic reticulum remodeling, ER-phagy, and Collagen quality control
- term:
    id: GO:0061709
    label: reticulophagy
  evidence_type: IMP
  original_reference_id: PMID:34338405
  qualifier: involved_in
  review:
    summary: RETREG2/FAM134A is an ER-phagy receptor that induces ER fragmentation and lysosomal degradation of ER material after autophagy induction or ER stress.
    action: NEW
    reason: PN correctly identified reticulophagy as the specific BP missing from the review/GOA. The existing GOA captures the ER-autophagosome adaptor MF and generic substrate localization to autophagosome, but not the specific ER-phagy process.
    supported_by:
    - reference_id: PMID:34338405
      supporting_text: We identify FAM134A/RETREG2 and FAM134C/RETREG3 as ER-phagy receptors
      reference_section_type: ABSTRACT
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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:21900206
  title: A directed protein interaction network for investigating intracellular signal
    transduction.
  findings: []
- id: PMID:26040720
  title: Regulation of endoplasmic reticulum turnover by selective autophagy.
  findings:
  - statement: The FAM134/RETREG family are ER-resident selective-autophagy receptors that bind ATG8/LC3 to drive ER turnover (ER-phagy).
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational ER-phagy paper establishing the FAM134 family (including FAM134A/RETREG2) as ER-phagy receptors. Abstract-only in cache.
- id: PMID:34338405
  title: Role of FAM134 paralogues in endoplasmic reticulum remodeling, ER-phagy,
    and Collagen quality control.
  findings:
  - statement: RETREG2/FAM134A is an ER-anchored autophagy regulator, inactive basally and activated by cellular stress, that induces ER fragmentation and delivers ER into lysosomes via autophagosomal sequestration (ATG8 interaction); FAM134 paralogues function in ER remodeling and collagen quality control.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available. Establishes RETREG2/FAM134A-specific ER-phagy function, stress-activation, ER membrane localization, and collagen quality control role.
core_functions:
- description: Functions as an ER membrane-anchored selective-autophagy (ER-phagy/reticulophagy) receptor that, upon stress activation, bridges the endoplasmic reticulum to autophagosomes through its LIR motif binding ATG8-family proteins (LC3/GABARAP), promoting ER fragmentation and delivery of ER fragments to lysosomes for degradation.
  molecular_function:
    id: GO:0140506
    label: endoplasmic reticulum-autophagosome adaptor activity
  supported_by:
  - reference_id: file:human/RETREG2/RETREG2-uniprot.txt
    supporting_text: mediates ER delivery into lysosomes through sequestration into autophagosomes via interaction with ATG8 family proteins
  - reference_id: file:human/RETREG2/RETREG2-uniprot.txt
    supporting_text: 'DOMAIN: The LIR motif interacts with ATG8 family proteins'
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  directly_involved_in:
  - id: GO:0061709
    label: reticulophagy
  - id: GO:0061753
    label: substrate localization to autophagosome
suggested_questions:
- question: What stress signals and post-translational modifications switch RETREG2/FAM134A from its inactive basal state to the active ER-phagy-competent state, and how does this differ from its paralogues RETREG1/FAM134B and RETREG3/FAM134C?
- question: How does RETREG2 mediate LIR-independent collagen quality control, and is this mechanistically separable from its canonical LIR-dependent ER-phagy?
suggested_experiments:
- description: Compare ER-phagy flux and ER membrane fragmentation in cells expressing wild-type versus LIR-mutant RETREG2 under basal and stress (e.g. ER-stress/starvation) conditions, using ER-phagy reporters, to define LIR-dependent versus -independent activities.
- description: Perform reconstitution and structure-function analysis of the RETREG2 reticulon-homology domain to test its membrane-curvature/scission activity and its requirement for ER fragmentation during ER-phagy.