ATG16L2 is the paralog of the autophagy protein ATG16L1, with an N-terminal ATG5-binding region, a coiled-coil that self-oligomerizes, and C-terminal WD repeats. Like ATG16L1, it binds ATG5 and forms a ~800-kDa ATG12-ATG5-ATG16L2 complex with E3-like activity in vitro. Unlike ATG16L1, it is not recruited to phagophores, stays mostly cytosolic, and is not required for canonical autophagosome formation. In mice it has lineage-specific roles in myeloid, lymphoid and epithelial cells. It is reported to support ATG5-12-16L1 assembly and autophagy flux in LPS-stimulated macrophages, which restrains NLRP3 inflammasome activation, and to promote NLRC4 inflammasome activation by binding NAIPs. ATG16L2 variants are associated with Crohn disease and systemic lupus erythematosus.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000045 autophagosome assembly | ISS NOT GO_REF:0000024 | ACCEPT | Summary: NOT involved in autophagosome assembly (ISS, from mouse). Atg16L2 is not recruited to phagophores, cannot substitute for Atg16L1 in autophagosome formation, and is not required for canonical autophagy, even though it forms an Atg12-5-16L2 complex. Accepted as a negative statement. Later work suggests it may influence ATG16L1 complex assembly, but that is regulation, not a direct role in assembling the autophagosome. Reason: [PMID:22082872 "A subcellular distribution analysis indicated that, despite forming the Atg12–5-16L2 complex, Atg16L2 is not recruited to phagophores and is mostly present in the cytosol."] [PMID:22082872 "Based on these results, we concluded that Atg16L2 is not required for canonical autophagy, despite forming an ~800-kDa complex with Atg12–5 and having E3-like activity."] [file:human/ATG16L2/ATG16L2-uniprot.txt "CC ATG16L2 is not essential for canonical autophagy."] Supporting Evidence: PMID:22082872 A subcellular distribution analysis indicated that, despite forming the Atg12–5-16L2 complex, Atg16L2 is not recruited to phagophores and is mostly present in the cytosol. PMID:22082872 Based on these results, we concluded that Atg16L2 is not required for canonical autophagy, despite forming an ~800-kDa complex with Atg12–5 and having E3-like activity. file:human/ATG16L2/ATG16L2-uniprot.txt CC ATG16L2 is not essential for canonical autophagy. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | UNDECIDED | Summary: Nucleoplasm (IDA, Human Protein Atlas immunofluorescence). In mouse cells, nuclear signal from EGFP-tagged Atg16L2 was judged a tagging artifact, because HA-tagged protein was cytosolic and absent from the nucleus. The HPA antibody result is independent (I did not check its HPA reliability score), but none of the cited studies confirms a nuclear pool or function. Undecided. Reason: [PMID:22082872 "EGFP-Atg16L2 also appeared to be present in the nucleus, but its apparent nuclear localization of EGFP-Atg16L2 may have been an artifact of EGFP-tagging, because HA-tagged Atg16L2 showed clear cytosolic localization and did not accumulate in the nucleus (data not shown)."] Supporting Evidence: PMID:22082872 EGFP-Atg16L2 also appeared to be present in the nucleus, but its apparent nuclear localization of EGFP-Atg16L2 may have been an artifact of EGFP-tagging, because HA-tagged Atg16L2 showed clear cytosolic localization and did not accumulate in the nucleus (data not shown). |
| GO:0005776 autophagosome | ISS NOT GO_REF:0000024 | ACCEPT | Summary: NOT located in autophagosome (ISS, from mouse). Atg16L2 is not recruited to phagophores and stays mostly cytosolic. Accepted as a negative statement. Reason: [PMID:22082872 "A subcellular distribution analysis indicated that, despite forming the Atg12–5-16L2 complex, Atg16L2 is not recruited to phagophores and is mostly present in the cytosol."] Supporting Evidence: PMID:22082872 A subcellular distribution analysis indicated that, despite forming the Atg12–5-16L2 complex, Atg16L2 is not recruited to phagophores and is mostly present in the cytosol. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Cytosol (IEA, UniProt subcellular location). Atg16L2 is mostly cytosolic, where it forms its complex with Atg12-Atg5. Core location. Reason: [PMID:22082872 "A subcellular distribution analysis indicated that, despite forming the Atg12–5-16L2 complex, Atg16L2 is not recruited to phagophores and is mostly present in the cytosol."] Supporting Evidence: PMID:22082872 A subcellular distribution analysis indicated that, despite forming the Atg12–5-16L2 complex, Atg16L2 is not recruited to phagophores and is mostly present in the cytosol. file:human/ATG16L2/ATG16L2-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | ISS GO_REF:0000024 | ACCEPT | Summary: Cytosol (ISS, from mouse). Atg16L2 is mostly cytosolic, where it forms its complex with Atg12-Atg5. Core location. Reason: [PMID:22082872 "A subcellular distribution analysis indicated that, despite forming the Atg12–5-16L2 complex, Atg16L2 is not recruited to phagophores and is mostly present in the cytosol."] Supporting Evidence: PMID:22082872 A subcellular distribution analysis indicated that, despite forming the Atg12–5-16L2 complex, Atg16L2 is not recruited to phagophores and is mostly present in the cytosol. file:human/ATG16L2/ATG16L2-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9936620 | ACCEPT | Summary: Cytosol (TAS, Reactome). Atg16L2 is mostly cytosolic, where it forms its complex with Atg12-Atg5; the Reactome event depicts ATG5:ATG12 binding ATG16L2. Core location. Reason: [PMID:22082872 "A subcellular distribution analysis indicated that, despite forming the Atg12–5-16L2 complex, Atg16L2 is not recruited to phagophores and is mostly present in the cytosol."] [file:reactome/R-HSA-9936620.md "display_name: ATG5:ATG12 binds ATG16L2"] Supporting Evidence: PMID:22082872 A subcellular distribution analysis indicated that, despite forming the Atg12–5-16L2 complex, Atg16L2 is not recruited to phagophores and is mostly present in the cytosol. file:reactome/R-HSA-9936620.md display_name: ATG5:ATG12 binds ATG16L2 |
| GO:0006914 autophagy | ISS NOT GO_REF:0000024 | ACCEPT | Summary: NOT involved in autophagy (ISS, from mouse). Atg16L2 is dispensable for canonical starvation-induced autophagy and is not recruited to phagophores. Later knockouts report that ATG16L2 loss reduces LPS-induced autophagy flux in macrophages by impairing ATG5-12-16L1 assembly. That mechanism acts on the ATG16L1 complex, so it is regulation of autophagy, which an involved_in annotation does not cover. It is therefore compatible with this NOT row, as for the NOT autophagosome assembly row. Accepted as a negative statement for direct participation; a positive-regulation term would be a separate question. Reason: [PMID:22082872 "Based on these results, we concluded that Atg16L2 is not required for canonical autophagy, despite forming an ~800-kDa complex with Atg12–5 and having E3-like activity."] [PMID:22082872 "A subcellular distribution analysis indicated that, despite forming the Atg12–5-16L2 complex, Atg16L2 is not recruited to phagophores and is mostly present in the cytosol."] [PMID:35426127 "Here we report that ATG16L2 deficiency attenuates LPS-induced autophagy flux in macrophages through mediating ATG5-12-16L1 complex assembly."] [PMID:35426127 "Collectively, our data demonstrate that ATG16L2 positively regulates autophagy and ATG16L2 could be a potential target for manipulating aberrant NLRP3 inflammasome activation induced inflammatory diseases."] Supporting Evidence: PMID:22082872 Based on these results, we concluded that Atg16L2 is not required for canonical autophagy, despite forming an ~800-kDa complex with Atg12–5 and having E3-like activity. PMID:22082872 A subcellular distribution analysis indicated that, despite forming the Atg12–5-16L2 complex, Atg16L2 is not recruited to phagophores and is mostly present in the cytosol. PMID:35426127 Here we report that ATG16L2 deficiency attenuates LPS-induced autophagy flux in macrophages through mediating ATG5-12-16L1 complex assembly. PMID:35426127 Collectively, our data demonstrate that ATG16L2 positively regulates autophagy and ATG16L2 could be a potential target for manipulating aberrant NLRP3 inflammasome activation induced inflammatory diseases. |
| GO:0034274 Atg12-Atg5-Atg16 complex | IEA GO_REF:0000117 | ACCEPT | Summary: Atg12-Atg5-Atg16 complex (IEA). ATG16L2 binds ATG5 and self-oligomerizes into an ~800-kDa complex with Atg12-Atg5, which is absent in Atg5-knockout cells. Core. Reason: [PMID:22082872 "Biochemical analysis revealed that Atg16L2 interacts with Atg5 and self-oligomerizes to form an ~800-kDa complex, the same as Atg16L1 does."] [file:human/ATG16L2/ATG16L2-uniprot.txt "CC ATG5. Self-oligomerizes to form a 800-kDa complex composed of ATG12-"] Supporting Evidence: PMID:22082872 Biochemical analysis revealed that Atg16L2 interacts with Atg5 and self-oligomerizes to form an ~800-kDa complex, the same as Atg16L1 does. file:human/ATG16L2/ATG16L2-uniprot.txt CC ATG5. Self-oligomerizes to form a 800-kDa complex composed of ATG12- |
| GO:0034274 Atg12-Atg5-Atg16 complex | IPI PMID:23202584 Structure of the human ATG12~ATG5 conjugate required for LC3... | ACCEPT | Summary: Atg12-Atg5-Atg16 complex (IPI). ATG16L2 binds ATG5 and self-oligomerizes into an ~800-kDa complex with Atg12-Atg5, which is absent in Atg5-knockout cells. The cached text of this structural paper on the ATG12~ATG5-ATG16L1 conjugate does not mention ATG16L2, so the curator's evidence is presumably in material not cached. The complex is independently established. Core. Reason: [PMID:22082872 "Biochemical analysis revealed that Atg16L2 interacts with Atg5 and self-oligomerizes to form an ~800-kDa complex, the same as Atg16L1 does."] [file:human/ATG16L2/ATG16L2-uniprot.txt "CC ATG5. Self-oligomerizes to form a 800-kDa complex composed of ATG12-"] Supporting Evidence: PMID:22082872 Biochemical analysis revealed that Atg16L2 interacts with Atg5 and self-oligomerizes to form an ~800-kDa complex, the same as Atg16L1 does. file:human/ATG16L2/ATG16L2-uniprot.txt CC ATG5. Self-oligomerizes to form a 800-kDa complex composed of ATG12- |
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Download this section (compressed HTML)Q: Does the ATG12-ATG5-ATG16L2 complex lipidate LC3 on any non-canonical membrane (for example during LC3-associated phagocytosis), and do Crohn disease-associated ATG16L2 variants alter that?
Experiment: In ATG16L1-null human cells re-expressing ATG16L2, test LC3 lipidation on phagosomes, endolysosomes and in CASM, and map the region (as in the Atg16L1/L2 chimeras) that would confer membrane recruitment.
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: What the cytosolic ATG12-ATG5-ATG16L2 complex does, given that it has E3-like activity in vitro but is not recruited to phagophores, is unknown.
OPEN BIOLOGY MF_DARK
What is known: Established: complex formation, cytosolic localization and dispensability for canonical autophagosome formation (mouse cells). Reported, abstract-only: effects on ATG16L1 complex assembly and on NLRP3 and NLRC4 inflammasome activation in mouse macrophages. Not established: any membrane target of the ATG16L2 complex, the mechanism of its inflammasome effects, or whether these hold in human cells.
Provenance (the field's own admissions):
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