The Autophagy-Initiating Kinase ULK1 Controls RIPK1-Mediated Cell Death

Cell Rep. 2020 Apr 21;31(3):107547. doi: 10.1016/j.celrep.2020.107547.

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.

Keywords: MLKL; RIPK1; RIPK3; TNF; ULK1; autophagy; complex I; complex II; necroptosis; necrosome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy
  • Autophagy-Related Protein-1 Homolog / metabolism*
  • Cell Death / physiology
  • Cell Line
  • Cell Line, Tumor
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Phosphorylation
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction

Substances

  • Intracellular Signaling Peptides and Proteins
  • Autophagy-Related Protein-1 Homolog
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • ULK1 protein, human