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

Abstract

Mutations in MEFV, the gene encoding pyrin in humans, are associated with the autoinflammatory disorder familial Mediterranean fever. Pyrin is an innate sensor that assembles into an inflammasome complex in response to Rho-modifying toxins, including Clostridium difficile toxins A and B. Cell death pathways have been shown to intersect with and modulate inflammasome activation, thereby affecting host defense. Using bone marrow-derived macrophages and a murine model of peritonitis, we show in this study that receptor-interacting protein kinase (RIPK) 3 impacts pyrin inflammasome activation independent of its role in necroptosis. RIPK3 was instead required for transcriptional upregulation of Mefv through negative control of the mechanistic target of rapamycin (mTOR) pathway and independent of alterations in MAPK and NF-κB signaling. RIPK3 did not affect pyrin dephosphorylation associated with inflammasome activation. We further demonstrate that inhibition of mTOR was sufficient to promote Mefv expression and pyrin inflammasome activation, highlighting the cross-talk between the mTOR pathway and regulation of the pyrin inflammasome. Our study reveals a novel interaction between molecules involved in cell death and the mTOR pathway to regulate the pyrin inflammasome, which can be harnessed for therapeutic interventions.

• Authors: Deepika Sharma, Ankit Malik, Arjun Balakrishnan, R K Subbarao Malireddi, Thirumala-Devi Kanneganti
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 205 Issue 10 Pg. 2778-2785 (11 15 2020) ISSN: 1550-6606 [Electronic] United States
• PMID: 32989095 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 by The American Association of Immunologists, Inc.

Chemical References

• Bacterial Proteins
• Bacterial Toxins
• Enterotoxins
• Inflammasomes
• Mefv protein, mouse
• Pyrin
• tcdA protein, Clostridium difficile
• toxB protein, Clostridium difficile
• mTOR protein, mouse
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk3 protein, mouse
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Animals
• Apoptosis (immunology)
• Bacterial Proteins (administration & dosage, immunology)
• Bacterial Toxins (administration & dosage, immunology)
• Cells, Cultured
• Disease Models, Animal
• Enterotoxins (administration & dosage, immunology)
• Familial Mediterranean Fever (genetics, immunology)
• Humans
• Inflammasomes (drug effects, immunology, metabolism)
• Macrophages
• Mice
• Mice, Knockout
• Mutation
• Necroptosis (immunology)
• Peritonitis (immunology, microbiology)
• Phosphorylation (immunology)
• Primary Cell Culture
• Pyrin (genetics, metabolism)
• Receptor-Interacting Protein Serine-Threonine Kinases (genetics, metabolism)
• Signal Transduction (drug effects, immunology)
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Transcriptional Activation (immunology)
• Up-Regulation