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Updated: Dec 7, 2025

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

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RIPK3 Promotes Mefv Expression and Pyrin Inflammasome Activation via Modulation of mTOR Signaling

Deepika Sharma1, Ankit Malik1, Arjun Balakrishnan1

  • 1Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.

Journal of Immunology (Baltimore, Md. : 1950)
|September 29, 2020
PubMed

Insights

Receptor-interacting protein kinase 3 (RIPK3) regulates pyrin inflammasome activation by controlling MEFV gene expression via the mTOR pathway, independent of necroptosis. This finding reveals a novel link between cell death and mTOR signaling for potential therapeutic strategies.

Area of Science:

  • Immunology
  • Cell Biology
  • Genetics

Background:

  • Familial Mediterranean Fever (FMF) is linked to mutations in the MEFV gene, which encodes pyrin.
  • Pyrin is an innate immune sensor forming inflammasomes in response to toxins like Clostridium difficile toxins A and B.
  • Cell death pathways influence inflammasome activation and host defense.

Purpose of the Study:

  • To investigate the role of receptor-interacting protein kinase 3 (RIPK3) in pyrin inflammasome activation.
  • To elucidate the mechanisms by which RIPK3 regulates MEFV expression and pyrin inflammasome assembly.
  • To explore the interplay between cell death pathways, mTOR signaling, and pyrin inflammasome regulation.

Main Methods:

  • Utilized bone marrow-derived macrophages and a murine model of peritonitis.
  • Assessed the impact of RIPK3 on pyrin inflammasome activation.
  • Investigated the transcriptional regulation of MEFV, including the roles of mTOR, MAPK, and NF-κB signaling pathways.
  • Examined pyrin dephosphorylation in relation to inflammasome activation.

Main Results:

  • RIPK3 promotes pyrin inflammasome activation independently of its role in necroptosis.
  • RIPK3 upregulates MEFV transcription by negatively regulating the mechanistic target of rapamycin (mTOR) pathway.
  • RIPK3's effect on MEFV expression is independent of MAPK and NF-κB signaling alterations.
  • Inhibition of mTOR is sufficient to enhance MEFV expression and pyrin inflammasome activation.

Conclusions:

  • RIPK3 plays a crucial role in pyrin inflammasome activation through mTOR-dependent transcriptional control of MEFV.
  • A novel crosstalk exists between cell death pathways, the mTOR pathway, and pyrin inflammasome regulation.
  • These findings offer potential therapeutic targets for autoinflammatory disorders involving the pyrin inflammasome.

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