Journal
JOURNAL OF IMMUNOLOGY
Volume 193, Issue 4, Pages 1539-1543Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1400590
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Funding
- National Institutes of Health/National Institute of Allergy and Infectious Diseases [AI075118]
- European Research Council [2012-ADG_20120314]
- German Research Foundation [SFB670, SFB829, SPP1656]
- European Commission [223404, 223151]
- Deutsche Krebshilfe [110302]
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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 NF kappa B 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.
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