AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy

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&#...

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Veröffentlicht in:Science advances 2021-04, Vol.7 (15)
Hauptverfasser: Hung, Chien-Min, Lombardo, Portia S, Malik, Nazma, Brun, Sonja N, Hellberg, Kristina, Van Nostrand, Jeanine L, Garcia, Daniel, Baumgart, Joshua, Diffenderfer, Ken, Asara, John M, Shaw, Reuben J
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container_issue 15
container_start_page
container_title Science advances
container_volume 7
creator Hung, Chien-Min
Lombardo, Portia S
Malik, Nazma
Brun, Sonja N
Hellberg, Kristina
Van Nostrand, Jeanine L
Garcia, Daniel
Baumgart, Joshua
Diffenderfer, Ken
Asara, John M
Shaw, Reuben J
description 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.
doi_str_mv 10.1126/sciadv.abg4544
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SciAdv r-articles
title AMPK/ULK1-mediated phosphorylation of Parkin ACT domain mediates an early step in mitophagy
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