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Identification of PPM1D as an essential Ulk1 phosphatase for genotoxic stress‐induced autophagy
Author(s) -
Torii Satoru,
Yoshida Tatsushi,
Arakawa Satoko,
Honda Shinya,
Nakanishi Akira,
Shimizu Shigeomi
Publication year - 2016
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201642565
Subject(s) - ulk1 , autophagy , dephosphorylation , microbiology and biotechnology , biology , phosphatase , chemistry , phosphorylation , biochemistry , apoptosis , protein kinase a , ampk
Autophagy is an evolutionary conserved process that degrades subcellular constituents. Unlike starvation‐induced autophagy, the molecular mechanism of genotoxic stress‐induced autophagy has not yet been fully elucidated. In this study, we analyze the molecular mechanism of genotoxic stress‐induced autophagy and identify an essential role of dephosphorylation of the Unc51‐like kinase 1 (Ulk1) at Ser 637 , which is catalyzed by the protein phosphatase 1D magnesium‐dependent delta isoform (PPM1D). We show that after exposure to genotoxic stress, PPM1D interacts with and dephosphorylates Ulk1 at Ser 637 in a p53‐dependent manner. The PPM1D‐dependent Ulk1 dephosphorylation triggers Ulk1 puncta formation and induces autophagy. This happens not only in mouse embryonic fibroblasts but also in primary thymocytes, where the genetic ablation of PPM1D reduces the dephosphorylation of Ulk1 at Ser 637 , inhibits autophagy, and accelerates apoptosis induced by X‐ray irradiation. This acceleration of apoptosis is caused mainly by the inability of the autophagic machinery to degrade the proapoptotic molecule Noxa. These findings indicate that the PPM1D–Ulk1 axis plays a pivotal role in genotoxic stress‐induced autophagy.