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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Polykratis, A; Hermance, N; Zelic, M; Roderick, J; Kim, C; Van, T-M; Lee, TH; Chan, FKM; Pasparakis, M; Kelliher, MA

Published Date

  • August 15, 2014

Published In

Volume / Issue

  • 193 / 4

Start / End Page

  • 1539 - 1543

PubMed ID

  • 25015821

Pubmed Central ID

  • 25015821

Electronic International Standard Serial Number (EISSN)

  • 1550-6606

Digital Object Identifier (DOI)

  • 10.4049/jimmunol.1400590

Language

  • eng

Conference Location

  • United States