Wu Wenxian, Wang Xiaojing, Berleth Niklas, Deitersen Jana, Wallot-Hieke Nora, Böhler Philip, Schlütermann David, Stuhldreier Fabian, Cox Jan, Schmitz Katharina, Seggewiß Sabine, Peter Christoph, Kasof Gary, Stefanski Anja, Stühler Kai, Tschapek Astrid, Gödecke Axel, Stork Björn
Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
Cell Signaling Technology, Danvers, MA 01923, USA.
Cell Rep. 2020 Apr 21;31(3):107547. doi: 10.1016/j.celrep.2020.107547.
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.
自噬、凋亡和坏死性凋亡是决定细胞最终命运的应激反应。然而，这些细胞应激反应之间的相互作用尚未完全明确。特别是，自噬起始激酶ULK1和细胞死亡调节激酶RIPK1是否参与这种潜在的相互作用尚不清楚。在此，我们确定RIPK1是ULK1的底物。ULK1依赖性的RIPK1磷酸化减少了复合物IIb/坏死小体的组装以及肿瘤坏死因子（TNF）诱导的细胞死亡，而ULK1的缺失则增强了TNF诱导的细胞死亡。我们观察到ULK1使RIPK1的多个位点磷酸化，但似乎特别是RIPK1中间结构域内S357的磷酸化介导了这种细胞死亡抑制作用。我们提出ULK1是RIPK1介导的细胞死亡的调节因子。
