Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis

Cell Death Dis. 2018 May 22;9(6):592. doi: 10.1038/s41419-018-0672-0.

Abstract

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cytokines / biosynthesis*
  • Inhibitor of Apoptosis Proteins / metabolism
  • Lysine / metabolism
  • Mice, Inbred C57BL
  • Necrosis
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Proteolysis*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Cytokines
  • Inhibitor of Apoptosis Proteins
  • RNF216 protein, mouse
  • Ubiquitin-Protein Ligases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • Ripk3 protein, mouse
  • Proteasome Endopeptidase Complex
  • Lysine