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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016020 membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference of membrane localization; correct but a generic parent of the specific ER membrane localization. Reason: Correct but overly generic; the specific endoplasmic reticulum membrane annotation captures RETREG2's actual localization. Supporting Evidence: file:human/RETREG2/RETREG2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of ER membrane localization from UniProt; the correct core compartment, redundant with experimental EXP evidence. Reason: Core localization; RETREG2 is a multi-pass ER membrane protein that acts as an ER-phagy receptor. Supporting Evidence: file:human/RETREG2/RETREG2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:34338405} |
| GO:0061753 substrate localization to autophagosome | IEA GO_REF:0000108 | ACCEPT | Summary: Inter-ontology logical inference of substrate localization to autophagosome; consistent with RETREG2 delivering ER fragments into autophagosomes. Reason: Core process; RETREG2 sequesters ER substrate into autophagosomes via its LIR-ATG8 interaction during ER-phagy. Supporting Evidence: file:human/RETREG2/RETREG2-uniprot.txt mediates ER delivery into lysosomes through sequestration into autophagosomes via interaction with ATG8 family proteins |
| GO:0005515 protein binding | IPI PMID:21900206 A directed protein interaction network for investigating int... | KEEP AS NON CORE | Summary: High-throughput directed protein-interaction-network interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:26040720 Regulation of endoplasmic reticulum turnover by selective au... | KEEP AS NON CORE | Summary: Interaction(s) from the foundational ER-phagy/FAM134 selective-autophagy study (e.g. ATG8/LC3 family). Bare protein binding is uninformative. Reason: Records functionally relevant ER-phagy interactions but the bare term is uninformative; the ER-autophagosome adaptor activity annotation captures the function. Supporting Evidence: PMID:26040720 Regulation of endoplasmic reticulum turnover by selective autophagy |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic assignment of endoplasmic reticulum localization; correct but a generic parent of the specific ER membrane localization. Reason: Correct but overly generic; the specific ER membrane annotation captures RETREG2's localization as a multi-pass ER membrane protein. Supporting Evidence: file:human/RETREG2/RETREG2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0140506 endoplasmic reticulum-autophagosome adaptor activity | IEA GO_REF:0000107 | ACCEPT | 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. 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. Supporting Evidence: file:human/RETREG2/RETREG2-uniprot.txt DOMAIN: The LIR motif interacts with ATG8 family proteins |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:34338405 Role of FAM134 paralogues in endoplasmic reticulum remodelin... | ACCEPT | Summary: Experimental evidence (FAM134 paralogue study) for ER membrane localization of RETREG2/FAM134A. Core compartment. Reason: Direct experimental support for the core ER membrane localization where RETREG2 functions in ER-phagy. Supporting Evidence: PMID:34338405 Role of FAM134 paralogues in endoplasmic reticulum remodeling, ER-phagy, and Collagen quality control |
| GO:0061709 reticulophagy | IMP PMID:34338405 Role of FAM134 paralogues in endoplasmic reticulum remodelin... | NEW | Summary: RETREG2/FAM134A is an ER-phagy receptor that induces ER fragmentation and lysosomal degradation of ER material after autophagy induction or ER stress. 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. Supporting Evidence: PMID:34338405 We identify FAM134A/RETREG2 and FAM134C/RETREG3 as ER-phagy receptors |
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Download this section (compressed HTML)Q: 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?
Q: How does RETREG2 mediate LIR-independent collagen quality control, and is this mechanistically separable from its canonical LIR-dependent ER-phagy?
Experiment: 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.
Experiment: 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.
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