Raver1 links <i>Ripk1</i> RNA splicing to caspase-8-mediated pyroptotic cell death, inflammation, and pathogen resistance
Abstract
Multiple cell death and inflammatory signaling pathways converge on two critical factors: receptor-interacting serine/threonine kinase 1 (RIPK1) and caspase-8. Careful regulation of these molecules is critical to control apoptosis, pyroptosis, and inflammation. Here, we found a pivotal role of Raver1 as an essential regulator of Ripk1 pre-mRNA splicing, expression, and functionality and the subsequent caspase-8-dependent inflammatory cell death. We show that Raver1 influences mRNA diversity primarily by repressing alternative exon inclusion. Macrophages from Raver1 -deficient mice exhibit altered splicing of Ripk1 . As a result, Raver1 -deficient primary macrophages display diminished cell death and decreased interleukin-18 and interleukin-1ß production, when infected with Yersinia bacteria, or by restraining TGF-ß-activated kinase 1 or IKKβ in the presence of lipopolysaccharide, tumor necrosis factor family members, or interferon-γ. These responses are accompanied by reduced activation of caspase-8, Gasdermin D and E, and caspase-1 in the absence of Raver1 . Consequently, Raver1 -deficient mice showed heightened susceptibility to Yersinia infection. Raver1 and RIPK1 also controlled the expression and function of the C-type lectin receptor Mincle. Our study underscores the critical regulatory role of Raver1 in modulating innate immune responses and highlights its significance in directing in vivo and in vitro inflammatory processes.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Boyao Zhang
Division of Infectious Diseases and Immunology, Department of Medicine, Program in Innate Immunity, University of Massachusetts Chan Medical School
Pontus Orning
Division of Infectious Diseases and Immunology, Department of Medicine, Program in Innate Immunity, University of Massachusetts Chan Medical School
Jesse W. Lehman
RNA Therapeutics Institute, University of Massachusetts Chan Medical School
Alexandre Dinis
Division of Infectious Diseases and Immunology, Department of Medicine, Program in Innate Immunity, University of Massachusetts Chan Medical School
Leslie Torres-Ulloa
RNA Therapeutics Institute, University of Massachusetts Chan Medical School
Roland Elling
Institute for Immunodeficiency, Center of Chronic Immunodeficiency, University Medical Center, Faculty of Medicine, University of Freiburg
Michelle A. Kelliher
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School
John Bertin
Immunology and Inflammation Therapeutic Area, Sanofi
Megan K. Proulx
Department of Microbiology, University of Massachusetts Medical School
Jon D. Goguen
Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School
Liv Ryan
Department of Clinical and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology
Richard K. Kandasamy
Division of Infectious Diseases and Immunology, Department of Medicine, Program in Innate Immunity, University of Massachusetts Chan Medical School
Terje Espevik
Department of Clinical and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology
Athma A. Pai
RNA Therapeutics Institute, University of Massachusetts Chan Medical School
Katherine A. Fitzgerald
Department of Medicine, University of Massachusetts Chan Medical School
Egil Lien
Division of Infectious Diseases and Immunology, Department of Medicine, Program in Innate Immunity, University of Massachusetts Chan Medical School