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

Publication ,  Journal Article
Polykratis, A; Hermance, N; Zelic, M; Roderick, J; Kim, C; Van, T-M; Lee, TH; Chan, FKM; Pasparakis, M; Kelliher, MA
Published in: J Immunol
August 15, 2014

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.

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Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

August 15, 2014

Volume

193

Issue

4

Start / End Page

1539 / 1543

Location

United States

Related Subject Headings

  • Virus Replication
  • Vaccinia virus
  • Vaccinia
  • Tumor Necrosis Factor-alpha
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Poly I-C
  • Necrosis
  • NF-kappa B
  • Mice, Inbred C57BL
 

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Polykratis, A., Hermance, N., Zelic, M., Roderick, J., Kim, C., Van, T.-M., … Kelliher, M. A. (2014). Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo. J Immunol, 193(4), 1539–1543. https://doi.org/10.4049/jimmunol.1400590
Polykratis, Apostolos, Nicole Hermance, Matija Zelic, Justine Roderick, Chun Kim, Trieu-My Van, Thomas H. Lee, Francis K. M. Chan, Manolis Pasparakis, and Michelle A. Kelliher. “Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo.J Immunol 193, no. 4 (August 15, 2014): 1539–43. https://doi.org/10.4049/jimmunol.1400590.
Polykratis A, Hermance N, Zelic M, Roderick J, Kim C, Van T-M, et al. Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo. J Immunol. 2014 Aug 15;193(4):1539–43.
Polykratis, Apostolos, et al. “Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo.J Immunol, vol. 193, no. 4, Aug. 2014, pp. 1539–43. Pubmed, doi:10.4049/jimmunol.1400590.
Polykratis A, Hermance N, Zelic M, Roderick J, Kim C, Van T-M, Lee TH, Chan FKM, Pasparakis M, Kelliher MA. 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.

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

August 15, 2014

Volume

193

Issue

4

Start / End Page

1539 / 1543

Location

United States

Related Subject Headings

  • Virus Replication
  • Vaccinia virus
  • Vaccinia
  • Tumor Necrosis Factor-alpha
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Poly I-C
  • Necrosis
  • NF-kappa B
  • Mice, Inbred C57BL