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 Ngoc 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:28
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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