Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA.
Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD 20185, USA.
Sci Adv. 2021 Apr 23;7(17). doi: 10.1126/sciadv.abg4922. Print 2021 Apr.
Selective autophagy of damaged mitochondria, protein aggregates, and other cargoes is essential for health. Cargo initiates phagophore biogenesis, which entails the conjugation of LC3 to phosphatidylethanolamine. Current models suggest that clustered ubiquitin chains on a cargo trigger a cascade from autophagic cargo receptors through the core complexes ULK1 and class III phosphatidylinositol 3-kinase complex I, WIPI2, and the ATG7, ATG3, and ATG12ATG5-ATG16L1 machinery of LC3 lipidation. This was tested using giant unilamellar vesicles (GUVs), GST-Ub as a model cargo, the cargo receptors NDP52, TAX1BP1, and OPTN, and the autophagy core complexes. All three cargo receptors potently stimulated LC3 lipidation on GUVs. NDP52- and TAX1BP1-induced LC3 lipidation required all components, but not ULK1 kinase activity. However, OPTN bypassed the ULK1 requirement. Thus, cargo-dependent stimulation of LC3 lipidation is common to multiple autophagic cargo receptors, yet the details of core complex engagement vary between the different receptors.
选择性自噬受损线粒体、蛋白质聚集体和其他货物对于健康至关重要。货物启动噬菌体发生，这需要 LC3 与磷脂酰乙醇胺缀合。当前的模型表明，货物上聚集的泛素链触发了从自噬货物受体通过核心复合物 ULK1 和 III 类磷酸肌醇 3-激酶复合物 I、WIPI2 以及 ATG7、ATG3 和 ATG12-ATG5-ATG16L1 的 LC3 脂质化的级联反应。这是使用巨大单层囊泡 (GUV)、GST-Ub 作为模型货物、货物受体 NDP52、TAX1BP1 和 OPTN 以及自噬核心复合物进行测试的。所有三种货物受体都强烈刺激 GUV 上的 LC3 脂质化。NDP52 和 TAX1BP1 诱导的 LC3 脂质化需要所有成分，但不需要 ULK1 激酶活性。然而，OPTN 绕过了 ULK1 的要求。因此，多个自噬货物受体的 LC3 脂质化的货物依赖性刺激是常见的，但不同受体之间核心复合物的参与细节有所不同。
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