帕金
粒体自噬
品脱1
ULK1
细胞生物学
安普克
自噬
泛素连接酶
磷酸化
线粒体
生物
泛素
蛋白激酶A
化学
遗传学
帕金森病
医学
内科学
细胞凋亡
基因
疾病
作者
Chien-Min Hung,Portia S. Lombardo,Nazma Malik,Sonja N. Brun,Kristina Hellberg,Jeanine L. Van Nostrand,Daniel Garcia,Joshua T. Baumgart,Ken Diffenderfer,John M. Asara,Reuben J. Shaw
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2021-04-09
卷期号:7 (15)
被引量:75
标识
DOI:10.1126/sciadv.abg4544
摘要
The serine/threonine kinase ULK1 mediates autophagy initiation in response to various cellular stresses, and genetic deletion of ULK1 leads to accumulation of damaged mitochondria. Here we identify Parkin, the core ubiquitin ligase in mitophagy, and PARK2 gene product mutated in familial Parkinson's disease, as a ULK1 substrate. Recent studies uncovered a nine residue ("ACT") domain important for Parkin activation, and we demonstrate that AMPK-dependent ULK1 rapidly phosphorylates conserved serine108 in the ACT domain in response to mitochondrial stress. Phosphorylation of Parkin Ser108 occurs maximally within five minutes of mitochondrial damage, unlike activation of PINK1 and TBK1, which is observed thirty to sixty minutes later. Mutation of the ULK1 phosphorylation sites in Parkin, genetic AMPK or ULK1 depletion, or pharmacologic ULK1 inhibition, all lead to delays in Parkin activation and defects in assays of Parkin function and downstream mitophagy events. These findings reveal an unexpected first step in the mitophagy cascade.
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