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The RIPK1 death domain restrains ZBP1- and TRIF-mediated cell death and inflammation

Takashi Imai1, Juan Lin2, Göksu Gökberk Kaya1

  • 1Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.

Immunity
|May 14, 2024
PubMed

Insights

A mutation in RIPK1’s death domain (DD) caused lethal necroptosis in mice. This RIPK1 signaling is crucial for regulating inflammation and maintaining tissue homeostasis.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cell Biology

Background:

  • Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of cell death pathways, including apoptosis and necroptosis.
  • Its precise roles in kinase-dependent and -independent signaling remain incompletely understood.
  • Dysregulation of RIPK1 is implicated in inflammatory diseases.

Purpose of the Study:

  • To elucidate the physiological function of the RIPK1 death domain (DD) in regulating cell death and inflammation.
  • To investigate the mechanisms by which RIPK1 controls RIPK3 activation by ZBP1 and TRIF.
  • To determine the role of RIPK1 signaling in tissue homeostasis.

Main Methods:

  • Generation and analysis of mice with a mutation (R588E) in the RIPK1 death domain.
  • Biochemical assays to study RIPK1 kinase activity and protein interactions.
  • Investigation of necroptosis and inflammatory signaling pathways (ZBP1, TNFR1, TRIF, RIPK3, FADD).

Main Results:

  • Mice with the Ripk1 R588E mutation exhibited perinatal lethality due to ZBP1-mediated necroptosis.
  • These mice also developed postnatal inflammatory pathology independent of necroptosis, involving TNFR1, TRADD, and TRIF signaling, partially dependent on RIPK3.
  • RIPK1 kinase activity was essential for ZBP1- and TRIF-mediated RIPK3 activation in wild-type cells, but not in Ripk1R588E/R588E cells, indicating DD-dependent mechanisms.

Conclusions:

  • The RIPK1 death domain is critical for preventing lethal necroptosis and regulating postnatal inflammation.
  • DD-dependent RIPK1 oligomerization and FADD interaction dictate RIPK3 activation mechanisms.
  • RIPK1 signaling is vital for maintaining tissue homeostasis and controlling inflammatory responses.
Keywords:
FADDRIPK1TNFR1TRADDTRIFZBP1apoptosiscaspase-8inflammationnecroptosis

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