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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
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Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis

Kim Newton1, Debra L Dugger, Katherine E Wickliffe

  • 1Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.

Science (New York, N.Y.)
|February 22, 2014
PubMed

Insights

Receptor-interacting protein kinase 3 (RIPK3) kinase activity is essential for necroptosis. Inactive RIPK3 unexpectedly triggered apoptosis, while inactive RIPK1 blocked necroptosis but allowed other cell signaling pathways to function.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Death Pathways

Background:

  • Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 mediate necroptosis, a pro-inflammatory programmed cell death.
  • Previous studies using RIPK3-deficient mice or RIPK1 inhibitors suggested necroptosis contributes to disease pathology.

Purpose of the Study:

  • To investigate the necessity of active RIPK1 and RIPK3 kinase function in vivo.
  • To elucidate the distinct roles of RIPK1 and RIPK3 kinase activity in cell death and signaling.

Main Methods:

  • Engineering mice expressing catalytically inactive RIPK3 (D161N) and RIPK1 (D138N).
  • Assessing mouse viability, response to TNF-induced hypothermia, and cell death pathways (apoptosis and necroptosis).

Main Results:

  • Mice expressing inactive RIPK3 (D161N) exhibited lethal apoptosis dependent on RIPK1 and caspase-8.
  • Mice expressing inactive RIPK1 (D138N) were viable and resistant to TNF-induced hypothermia and necroptosis.
  • Cells with inactive RIPK1 (D138N) remained capable of TNF-induced gene transcription.

Conclusions:

  • RIPK3 kinase activity is indispensable for necroptosis.
  • RIPK3 kinase activity also regulates the switch between necroptosis and caspase-8-dependent apoptosis.
  • RIPK1 kinase activity is not essential for viability but is required for TNF-induced necroptosis.

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