SQST-1 is the C. elegans ortholog of mammalian p62/SQSTM1 and functions as a selective autophagy receptor. It contains conserved functional domains including a C-terminal UBA (ubiquitin-associated) domain that binds ubiquitinated cargo, an LIR (LC3-interacting region) motif for binding LGG-1/LGG-2 (Atg8/LC3 family proteins), a PB1 domain for self-oligomerization required for cargo clustering, and a ZZ-type zinc finger domain. SQST-1 bridges ubiquitinated protein aggregates to autophagosomes for degradation via aggrephagy, playing critical roles in proteostasis maintenance. SQST-1 accumulation (as puncta or protein levels) serves as a widely used readout for autophagic flux - accumulation indicates reduced flux, while decreased SQST-1 indicates increased flux.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0035973 aggrephagy | IBA GO_REF:0000033 | ACCEPT | Summary: Aggrephagy is a core function of SQST-1. The protein is required for degradation of ubiquitinated protein aggregates via selective autophagy. SQST-1 binds ubiquitinated cargo via its UBA domain and recruits autophagosomes via LGG-1 interaction. Reason: This is the primary biological process function of SQST-1. The deep research clearly establishes that SQST-1 binds ubiquitinated protein aggregates and delivers them to autophagosomes via LGG-1 interactions. The IBA inference from mammalian p62 is fully supported by direct experimental evidence in C. elegans. Supporting Evidence: PMID:23530068 epg-7 functions as a scaffold protein mediating autophagic degradation of several protein aggregates, including aggregates of the p62 homologue SQST-1 file:worm/sqst-1/sqst-1-deep-research-falcon.md As a selective autophagy receptor, SQST-1 bridges ubiquitinated cargoes to the autophagy machinery by binding ubiquitin via UBA and recruiting isolation membranes through LGG-1/Atg8 interaction via its LIR. Oligomerization (PB1) promotes phase separation/condensates and cargo clustering, facilitating autophagosome formation and turnover of aggregates (aggrephagy) |
| GO:0000423 mitophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: While mammalian p62/SQSTM1 has been implicated in mitophagy, direct experimental evidence for SQST-1 in C. elegans mitophagy is limited. The deep research notes that direct worm evidence for SQST-1's role in mitophagy remains less defined than aggrephagy. Reason: The IBA inference is phylogenetically sound given p62's role in mammalian mitophagy, but the primary worm literature emphasizes aggrephagy rather than mitophagy for SQST-1. Reviews infer conserved roles in organelle quality control based on domain conservation, but worm-specific mitophagy by SQST-1 has not been directly demonstrated. This is a plausible secondary function inferred from orthology rather than a demonstrated core function in C. elegans. Supporting Evidence: file:worm/sqst-1/sqst-1-deep-research-falcon.md direct worm evidence for SQST-1's role in mitophagy or specific organelle-selective autophagy remains less defined than aggrephagy in the curated set |
| GO:0005080 protein kinase C binding | IBA GO_REF:0000033 | UNDECIDED | Summary: Mammalian p62 interacts with atypical PKC isoforms via its PB1 domain. While SQST-1 contains a conserved PB1 domain that mediates self-oligomerization, direct evidence for PKC binding in C. elegans has not been reported in the literature reviewed. Reason: The IBA inference is based on mammalian p62 PKC interactions. SQST-1 has a PB1 domain and presumably retains similar binding capabilities, but no C. elegans-specific experimental evidence was found. The PB1 domain in worm literature is discussed primarily in the context of self-oligomerization for cargo clustering rather than PKC signaling. Without worm-specific data, this remains uncertain. Supporting Evidence: PMID:23530068 p62 contains a self-polymerization PB1 domain, a conserved LC3-interacting region (LIR), and a ubiquitin-associating (UBA) domain |
| GO:0007032 endosome organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Mammalian p62 has been implicated in endosomal trafficking, but this is not a well-documented function for C. elegans SQST-1. The primary literature on SQST-1 focuses on its role in autophagy and proteostasis rather than endosome organization. Reason: The IBA inference is phylogenetically sound but not supported by direct C. elegans evidence in the literature reviewed. SQST-1 is primarily studied in the context of autophagy in worms. This may be a peripheral function inferred from mammalian ortholog studies. |
| GO:0044753 amphisome | IBA GO_REF:0000033 | ACCEPT | Summary: Amphisomes are intermediate compartments formed by fusion of autophagosomes with endosomes before final lysosomal fusion. SQST-1 is documented to localize to autophagic structures that colocalize with LGG-1 puncta. Reason: Given SQST-1's role as an autophagy cargo receptor that bridges cargo to LGG-1-labeled autophagic structures, localization to amphisomes (intermediate autophagy compartments) is consistent with its function. The IBA inference aligns with experimental observations of SQST-1 colocalization with LGG-1 puncta in C. elegans. Supporting Evidence: file:worm/sqst-1/sqst-1-deep-research-falcon.md it forms puncta that frequently colocalize with LGG-1-labeled autophagic structures in adults. Accumulation of SQST-1 puncta/protein is a classic indicator of reduced autophagic flux |
| GO:0070530 K63-linked polyubiquitin modification-dependent protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: SQST-1 contains a conserved UBA domain (residues 654-693) that binds ubiquitin. The protein functions by binding ubiquitinated cargo for delivery to autophagosomes. Mammalian p62 shows preference for K63-linked ubiquitin chains. Reason: This molecular function is central to SQST-1's role as a selective autophagy receptor. The UBA domain is clearly documented in the UniProt record and functionally important for cargo recognition. While the specific K63-linkage preference has not been directly tested in C. elegans, the IBA inference from mammalian p62 is strongly supported by conservation of the UBA domain and the functional requirement for ubiquitin binding in aggrephagy. Supporting Evidence: PMID:23530068 p62 contains a self-polymerization PB1 domain, a conserved LC3-interacting region (LIR), and a ubiquitin-associating (UBA) domain file:worm/sqst-1/sqst-1-uniprot.txt DOMAIN 654..693 /note="UBA" /evidence="ECO:0000259|PROSITE:PS50030" |
| GO:0016235 aggresome | IBA GO_REF:0000033 | ACCEPT | Summary: SQST-1 is observed to form puncta/aggregates, particularly in autophagy mutants or under proteotoxic stress. These SQST-1-positive structures accumulate when autophagic flux is impaired and represent sites of cargo accumulation. Reason: SQST-1 puncta formation is extensively documented in C. elegans literature as a readout for autophagic flux. The protein accumulates into visible aggregates when autophagy is blocked, consistent with aggresome localization. This is experimentally validated in worm studies showing SQST-1::GFP puncta accumulation in autophagy mutants. Supporting Evidence: PMID:23530068 NA: SQST-1 aggregates are absent in wild-type embryos file:worm/sqst-1/sqst-1-deep-research-falcon.md Accumulation of SQST-1 puncta/protein is a classic indicator of reduced autophagic flux |
| GO:0008270 zinc ion binding | IEA GO_REF:0000120 | ACCEPT | Summary: SQST-1 contains a ZZ-type zinc finger domain (residues 179-229) as documented in UniProt. This domain coordinates zinc ions via conserved cysteine residues. Reason: The ZZ-type zinc finger domain is clearly present in the protein sequence and annotated in InterPro (IPR000433). The IEA inference from domain composition is valid. Supporting Evidence: file:worm/sqst-1/sqst-1-uniprot.txt DOMAIN 179..229 /note="ZZ-type" /evidence="ECO:0000259|PROSITE:PS50135" |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: This is a parent term of zinc ion binding. SQST-1 binds zinc via its ZZ-type zinc finger domain. Reason: This IEA is valid based on the zinc ion binding annotation. The broader metal ion binding term is subsumed by the more specific zinc ion binding annotation but is not incorrect. |
| GO:0005515 protein binding | IPI PMID:23530068 The scaffold protein EPG-7 links cargo-receptor complexes wi... | MODIFY | Summary: SQST-1 was shown to directly interact with EPG-7 (Q22342) and LGG-1 (O45995) by co-immunoprecipitation experiments. SQST-1 was specifically coimmunoprecipitated by anti-EPG-7 antibody from embryonic extracts. Reason: While the protein binding is experimentally demonstrated, this term is too general and uninformative. The specific interactions with EPG-7 (a scaffold protein) and LGG-1/Atg8 (via LIR motif) should be captured with more specific terms. The core molecular function of SQST-1 as an autophagy cargo adaptor is better represented by GO:0160247. Proposed replacements: autophagy cargo adaptor activity Supporting Evidence: PMID:23530068 SQST-1 was specifically coimmunoprecipitated by anti–EPG-7, but not by control IgG |
| GO:0005737 cytoplasm | IDA PMID:23530068 The scaffold protein EPG-7 links cargo-receptor complexes wi... | ACCEPT | Summary: Cytoplasmic localization of SQST-1 was directly observed using SQST-1::GFP reporters. The protein forms cytoplasmic puncta that colocalize with autophagic structures. Reason: Direct experimental evidence from microscopy of SQST-1::GFP reporters. The paper documents cytoplasmic localization and puncta formation. SQST-1 is diffusely cytoplasmic under normal conditions and forms puncta under stress or in autophagy mutants. Supporting Evidence: PMID:23530068 SQST-1 directly interacts with EPG-7 and colocalizes with EPG-7 aggregates in autophagy mutants |
| GO:0005737 cytoplasm | IDA PMID:21802374 The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates p... | ACCEPT | Summary: This publication (Lu et al. 2011) established the hierarchical relationship of autophagy genes in aggregate degradation. Cytoplasmic localization is implied by the use of autophagy reporters. Reason: Although PMID:21802374 focuses on EPG-6 and autophagosome formation, it uses autophagy reporters that display cytoplasmic localization. The duplicate annotation with the same GO term but different evidence sources is acceptable. Supporting Evidence: PMID:21802374 We also established the hierarchical relationship of autophagy genes in degradation of protein aggregates |
| GO:0160247 autophagy cargo adaptor activity | IDA PMID:23530068 The scaffold protein EPG-7 links cargo-receptor complexes wi... | NEW | Summary: SQST-1 functions as a selective autophagy receptor that bridges ubiquitinated cargo to the autophagy machinery. It binds ubiquitinated proteins via its UBA domain and recruits autophagosomes via LIR-mediated interaction with LGG-1/Atg8. This is the core molecular function that enables aggrephagy. Reason: This term precisely describes the core molecular function of SQST-1 as a cargo adaptor in selective autophagy. The existing GO annotations lack this key molecular function term. The experimental evidence directly supports this function. Supporting Evidence: PMID:23530068 A family of Atg8/LC3 (mammalian Atg8 homologue)-interacting proteins act as receptors that mediate delivery of specific cargoes to the autophagic machinery via Atg8/LC3 binding file:worm/sqst-1/sqst-1-deep-research-falcon.md As a selective autophagy receptor, SQST-1 bridges ubiquitinated cargoes to the autophagy machinery by binding ubiquitin via UBA and recruiting isolation membranes through LGG-1/Atg8 interaction via its LIR |
| GO:0005776 autophagosome | IDA PMID:23530068 The scaffold protein EPG-7 links cargo-receptor complexes wi... | NEW | Summary: SQST-1 colocalizes with LGG-1-labeled autophagosomes. SQST-1 aggregates associate with LGG-1 puncta during autophagic degradation. Reason: This cellular component annotation is directly supported by colocalization studies showing SQST-1 on autophagic structures. This is more informative than the existing cytoplasm annotation and complements the amphisome localization. Supporting Evidence: PMID:23530068 Mutations in epg-7 impair association of SQST-1 aggregates with LGG-1/Atg8 puncta |
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Download this section (compressed HTML)Q: Does SQST-1 participate in C. elegans mitophagy, or are there other selective autophagy receptors (e.g., DCT-1/BNIP3) that fulfill this role?
Q: What is the functional significance of the ZZ-type zinc finger domain in C. elegans SQST-1? Does it participate in signaling pathways similar to mammalian p62?
Q: Does SQST-1 interact with atypical PKC orthologs in C. elegans similar to mammalian p62-PKC interactions?
Experiment: Direct test of SQST-1 role in mitophagy using mitochondrial stress conditions and co-localization with mitophagy markers
Hypothesis: SQST-1 may participate in mitophagy in C. elegans similar to mammalian p62
Experiment: Biochemical characterization of ubiquitin chain-type specificity for SQST-1 UBA domain (K48 vs K63 vs linear chains)
Hypothesis: SQST-1 UBA domain preferentially binds K63-linked ubiquitin chains
Experiment: Structure-function analysis of SQST-1 ZZ domain to determine if it has signaling functions beyond autophagy in C. elegans
Hypothesis: The ZZ domain may have additional signaling roles beyond autophagy
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