2. Academic Validation
  3. 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
PMID: 28506461 DOI: 10.1016/j.molcel.2017.05.003
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
    99.70%, IKK Inhibitor
    IKK