The Autophagy-Initiating Kinase ULK1 Controls RIPK1-Mediated Cell Death
Wenxian Wu, Xiaojing Wang, Niklas Berleth, Jana Deitersen, Nora Hieke, Philip Böhler, David Schlütermann, Fabian Stuhldreier, Jan Cox, Katharina Schmitz, Sabine Seggewiß, Christoph Peter, Gary Kasof, Anja Stefanski, Kai Stühler, Astrid Tschapek, Axel Gödecke, Björn Stork
Abstract
Autophagy, apoptosis, and necroptosis are stress responses governing the ultimate fate of a cell. However, the crosstalk between these cellular stress responses is not entirely understood. Especially, it is not clear whether the autophagy-initiating kinase ULK1 and the cell-death-regulating kinase RIPK1 are involved in this potential crosstalk. Here, we identify RIPK1 as a substrate of ULK1. ULK1-dependent phosphorylation of RIPK1 reduces complex IIb/necrosome assembly and tumor necrosis factor (TNF)-induced cell death, whereas deprivation of ULK1 enhances TNF-induced cell death. We observe that ULK1 phosphorylates multiple sites of RIPK1, but it appears that especially phosphorylation of S357 within the intermediate domain of RIPK1 mediates this cell-death-inhibiting effect. We propose that ULK1 is a regulator of RIPK1-mediated cell death.