Identification of a phosphorylation site on Ulk1 required for genotoxic stress-induced alternative autophagy

Satoru Torii (), Hirofumi Yamaguchi, Akira Nakanishi, Satoko Arakawa, Shinya Honda, Kenta Moriwaki, Hiroyasu Nakano and Shigeomi Shimizu ()
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Satoru Torii: Tokyo Medical and Dental University (TMDU)
Hirofumi Yamaguchi: Tokyo Medical and Dental University (TMDU)
Akira Nakanishi: Tokyo Medical and Dental University (TMDU)
Satoko Arakawa: Tokyo Medical and Dental University (TMDU)
Shinya Honda: Tokyo Medical and Dental University (TMDU)
Kenta Moriwaki: Osaka University
Hiroyasu Nakano: Toho University School of Medicine
Shigeomi Shimizu: Tokyo Medical and Dental University (TMDU)

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: Abstract Alternative autophagy is an autophagy-related protein 5 (Atg5)-independent type of macroautophagy. Unc51-like kinase 1 (Ulk1) is an essential initiator not only for Atg5-dependent canonical autophagy but also for alternative autophagy. However, the mechanism as to how Ulk1 differentially regulates both types of autophagy has remained unclear. In this study, we identify a phosphorylation site of Ulk1 at Ser746, which is phosphorylated during genotoxic stress-induced alternative autophagy. Phospho-Ulk1746 localizes exclusively on the Golgi and is required for alternative autophagy, but not canonical autophagy. We also identify receptor-interacting protein kinase 3 (RIPK3) as the kinase responsible for genotoxic stress-induced Ulk1746 phosphorylation, because RIPK3 interacts with and phosphorylates Ulk1 at Ser746, and loss of RIPK3 abolishes Ulk1746 phosphorylation. These findings indicate that RIPK3-dependent Ulk1746 phosphorylation on the Golgi plays a pivotal role in genotoxic stress-induced alternative autophagy.

Date: 2020
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DOI: 10.1038/s41467-020-15577-2

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