Regulating RIPK1: another way in which ULK1 contributes to survival

Autophagy. 2020 Aug;16(8):1544-1546. doi: 10.1080/15548627.2020.1783110. Epub 2020 Jun 24.

Abstract

The mammalian ULK1 is the central initiating kinase of bulk and selective macroautophagy/autophagy processes. In the past, both autophagy-relevant and non-autophagy-relevant substrates of this Ser/Thr kinase have been reported. Here, we describe our recent finding that ULK1 also regulates TNF signaling pathways. We find that inhibition of autophagy or specifically ULK1 increases TNF-induced cell death. This autophagy-independent pro-survival function of ULK1 is mediated via the phosphorylation of RIPK1 at Ser357. RIPK1 is the central mediator of pro-inflammatory or pro-death signaling pathways induced by TNF, and ULK1-dependent phosphorylation regulates RIPK1 activation and distribution to different intracellular signaling complexes. Our results indicate that ULK1 exerts a cyto-protective function not only by initiating autophagy, but also by controlling RIPK1-mediated cell death.

Keywords: Autophagy; RIPK1; TNF; ULK1; necroptosis; necrosome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Autophagy-Related Protein-1 Homolog / metabolism*
  • Cell Survival
  • Cytoprotection
  • Humans
  • Necroptosis
  • Phosphorylation
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction

Substances

  • Autophagy-Related Protein-1 Homolog
  • Receptor-Interacting Protein Serine-Threonine Kinases

Grants and funding

This work was supported by the Deutsche Forschungsgemeinschaft [STO 864/4-1]; Deutsche Forschungsgemeinschaft [STO 864/5-1]; Deutsche Forschungsgemeinschaft [GRK 2158]; Düsseldorf School of Oncology [funded by the Comprehensive Cancer Center Düsseldorf/Deutsche Krebshilfe and the Medical Faculty of the Heinrich-Heine-University Düsseldorf; “Stress signaling in anticancer therapy resistance”].