粒体自噬
视神经肽
品脱1
自噬
帕金
生物
自噬体
细胞生物学
坦克结合激酶1
ULK1
袋3
激酶
ATG8型
蛋白激酶A
遗传学
帕金森病
MAP激酶激酶激酶
细胞凋亡
病理
疾病
医学
安普克
作者
Thanh N. Nguyen,Justyna Sawa-Makarska,Grace Khuu,Wai Kit Lam,Elias Adriaenssens,Dorotea Fracchiolla,Stephen Shoebridge,Daniel Bernklau,Benjamin Scott Padman,Marvin Skulsuppaisarn,Runa Lindblom,Sascha Martens,Michael Lazarou
出处
期刊:Molecular Cell
[Elsevier]
日期:2023-05-01
卷期号:83 (10): 1693-1709.e9
被引量:17
标识
DOI:10.1016/j.molcel.2023.04.021
摘要
Summary
Cargo sequestration is a fundamental step of selective autophagy in which cells generate a double-membrane structure termed an "autophagosome" on the surface of cargoes. NDP52, TAX1BP1, and p62 bind FIP200, which recruits the ULK1/2 complex to initiate autophagosome formation on cargoes. How OPTN initiates autophagosome formation during selective autophagy remains unknown despite its importance in neurodegeneration. Here, we uncover an unconventional path of PINK1/Parkin mitophagy initiation by OPTN that does not begin with FIP200 binding or require the ULK1/2 kinases. Using gene-edited cell lines and in vitro reconstitutions, we show that OPTN utilizes the kinase TBK1, which binds directly to the class III phosphatidylinositol 3-kinase complex I to initiate mitophagy. During NDP52 mitophagy initiation, TBK1 is functionally redundant with ULK1/2, classifying TBK1's role as a selective autophagy-initiating kinase. Overall, this work reveals that OPTN mitophagy initiation is mechanistically distinct and highlights the mechanistic plasticity of selective autophagy pathways.
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