Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo

J Immunol. 2014 Aug 15;193(4):1539-1543. doi: 10.4049/jimmunol.1400590. Epub 2014 Jul 11.

Abstract

The serine/threonine kinase RIPK1 is recruited to TNFR1 to mediate proinflammatory signaling and to regulate TNF-induced cell death. A RIPK1 deficiency results in perinatal lethality, impaired NFκB and MAPK signaling, and sensitivity to TNF-induced apoptosis. Chemical inhibitor and in vitro-reconstitution studies suggested that RIPK1 displays distinct kinase activity-dependent and -independent functions. To determine the contribution of RIPK1 kinase to inflammation in vivo, we generated knock-in mice endogenously expressing catalytically inactive RIPK1 D138N. Unlike Ripk1(-/-) mice, which die shortly after birth, Ripk1(D138N/D138N) mice are viable. Cells expressing RIPK1 D138N are resistant to TNF- and polyinosinic-polycytidylic acid-induced necroptosis in vitro, and Ripk1(D138N/D138N) mice are protected from TNF-induced shock in vivo. Moreover, Ripk1(D138N/D138N) mice fail to control vaccinia virus replication in vivo. This study provides genetic evidence that the kinase activity of RIPK1 is not required for survival but is essential for TNF-, TRIF-, and viral-initiated necroptosis.

Publication types

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

MeSH terms

  • Adaptor Proteins, Vesicular Transport / immunology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / immunology*
  • Cells, Cultured
  • Gene Knock-In Techniques
  • Hypothermia / chemically induced
  • Hypothermia / mortality*
  • Inflammation / genetics
  • Inflammation / immunology
  • MAP Kinase Signaling System / immunology
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / immunology
  • Necrosis / chemically induced
  • Necrosis / immunology*
  • Poly I-C / pharmacology
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
  • Receptor-Interacting Protein Serine-Threonine Kinases / immunology
  • Receptors, Tumor Necrosis Factor, Type I / immunology
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Vaccinia / immunology
  • Vaccinia virus / growth & development
  • Vaccinia virus / immunology
  • Virus Replication / immunology

Substances

  • Adaptor Proteins, Vesicular Transport
  • NF-kappa B
  • Receptors, Tumor Necrosis Factor, Type I
  • TICAM-1 protein, mouse
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • Ripk3 protein, mouse
  • Poly I-C