1. Academic Validation
  2. MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death

MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death

  • Mol Cell. 2017 Jun 1;66(5):698-710.e5. doi: 10.1016/j.molcel.2017.05.003.
Isabel Jaco 1 Alessandro Annibaldi 1 Najoua Lalaoui 2 Rebecca Wilson 1 Tencho Tenev 1 Lucie Laurien 3 Chun Kim 3 Kunzah Jamal 1 Sidonie Wicky John 1 Gianmaria Liccardi 1 Diep Chau 2 James M Murphy 2 Gabriela Brumatti 2 Rebecca Feltham 4 Manolis Pasparakis 5 John Silke 6 Pascal Meier 7
Affiliations

Affiliations

  • 1 Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, Fulham Road, London SW3 6JB, UK.
  • 2 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
  • 3 Institute for Genetics, University of Cologne, 50931 Cologne, Germany; Centre for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
  • 4 Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, Fulham Road, London SW3 6JB, UK; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
  • 5 Institute for Genetics, University of Cologne, 50931 Cologne, Germany; Centre for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. Electronic address: pasparakis@uni-koeln.de.
  • 6 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia. Electronic address: silke@wehi.edu.au.
  • 7 Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, Fulham Road, London SW3 6JB, UK. Electronic address: pmeier@icr.ac.uk.
Abstract

TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/Caspase-8 and induce RIPK1-kinase-dependent Apoptosis and Necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.

Keywords

IAPs; MK2; RIPK1; TNF; caspase-8; cell death; complex-II; cytokine; necroptosis; p38.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13019
    99.67%, IKK Inhibitor
    IKK