Cutting edge

RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice

Scott B. Berger, Viera Kasparcova, Sandy Hoffman, Barb Swift, Lauren Dare, Michelle Schaeffer, Carol Capriotti, Michael Cook, Joshua Finger, Angela Hughes-Earle, Philip A. Harris, William Kaiser, Edward S. Mocarski, John Bertin, Peter J. Gough

Research output: Contribution to journalArticle

167 Citations (Scopus)

Abstract

RIP1 (RIPK1) kinase is a key regulator of TNF-induced NF-κB activation, apoptosis, and necroptosis through its kinase and scaffolding activities. Dissecting the balance of RIP1 kinase activity and scaffolding function in vivo during development and TNF-dependent inflammation has been hampered by the perinatal lethality of RIP1-deficient mice. In this study, we generated RIP1 kinase-dead (Ripk1K45A) mice and showed they are viable and healthy, indicating that the kinase activity of RIP1, but not its scaffolding function, is dispensable for viability and homeostasis. After validating that the Ripk1K45A mice were specifically protected against necroptotic stimuli in vitro and in vivo, we crossed them with SHARPIN-deficient cpdm mice, which develop severe skin and multiorgan inflammation that has been hypothesized to be mediated by TNF-dependent apoptosis and/or necroptosis. Remarkably, crossing Ripk1K45A mice with the cpdm strain protected against all cpdmrelated pathology. Together, these data suggest that RIP1 kinase represents an attractive therapeutic target for TNF-driven inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)5476-5480
Number of pages5
JournalJournal of Immunology
Volume192
Issue number12
DOIs
StatePublished - Jun 15 2014
Externally publishedYes

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Phosphotransferases
Inflammation
Apoptosis
Homeostasis
Pathology
Skin
Therapeutics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Cutting edge : RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. / Berger, Scott B.; Kasparcova, Viera; Hoffman, Sandy; Swift, Barb; Dare, Lauren; Schaeffer, Michelle; Capriotti, Carol; Cook, Michael; Finger, Joshua; Hughes-Earle, Angela; Harris, Philip A.; Kaiser, William; Mocarski, Edward S.; Bertin, John; Gough, Peter J.

In: Journal of Immunology, Vol. 192, No. 12, 15.06.2014, p. 5476-5480.

Research output: Contribution to journalArticle

Berger, SB, Kasparcova, V, Hoffman, S, Swift, B, Dare, L, Schaeffer, M, Capriotti, C, Cook, M, Finger, J, Hughes-Earle, A, Harris, PA, Kaiser, W, Mocarski, ES, Bertin, J & Gough, PJ 2014, 'Cutting edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice', Journal of Immunology, vol. 192, no. 12, pp. 5476-5480. https://doi.org/10.4049/jimmunol.1400499
Berger, Scott B. ; Kasparcova, Viera ; Hoffman, Sandy ; Swift, Barb ; Dare, Lauren ; Schaeffer, Michelle ; Capriotti, Carol ; Cook, Michael ; Finger, Joshua ; Hughes-Earle, Angela ; Harris, Philip A. ; Kaiser, William ; Mocarski, Edward S. ; Bertin, John ; Gough, Peter J. / Cutting edge : RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. In: Journal of Immunology. 2014 ; Vol. 192, No. 12. pp. 5476-5480.
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