Identification of PPM1D as an essential Ulk1 phosphatase for genotoxic stress-induced autophagy.
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 Ser637, 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 Ser637in 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 Ser637, 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.
Department of Pathological Cell Biology, Medical Research Institute Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Satoru
S
Torii
Department of Pathological Cell Biology, Medical Research Institute Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Tatsushi
T
Yoshida
Department of Pathological Cell Biology, Medical Research Institute Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Satoko
S
Arakawa
Department of Pathological Cell Biology, Medical Research Institute Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Shinya
S
Honda
Department of Molecular Genetics, Medical Research Institute Tokyo Medical and Dental University, Tokyo, Japan.
Akira
A
Nakanishi
Department of Pathological Cell Biology, Medical Research Institute Tokyo Medical and Dental University (TMDU), Tokyo, Japan shimizu.pcb@mri.tmd.ac.jp.
Shigeomi
0000-0002-8437-0791
S
Shimizu
D000818:Animals; D001343:Autophagy / Q000235:genetics*; D000071189:Autophagy-Related Protein-1 Homolog / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055162:Biocatalysis; D004249:DNA Damage; D005347:Fibroblasts; D016158:Genes, p53; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D000071636:Protein Phosphatase 2C / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D060168:Thymocytes
C408009:Pmaip1 protein, mouse; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D000071189:Autophagy-Related Protein-1 Homolog; C112444:Ulk1 protein, mouse; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C; D008274:Magnesium
Noxa; PPM1D; Ulk1; autophagy; genotoxic stress
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