title: Cytochrome c Negatively Regulates NLRP3 Inflammasomes.
abstract: The release of cytochrome c from the inner mitochondrial membrane, where it is anchored by caridolipin, triggers the formation of the Apaf-1 apoptosome. Cardiolipin also interacts with NLRP3 recruiting NLRP3 to mitochondria and facilitating inflammasome assembly. In this study we investigated whether cytosolic cytochrome c impacts NLRP3 inflammasome activation in macrophages. We report that cytochrome c binds to the LRR domain of NLRP3 and that cytochrome c reduces the interactions between NLRP3 and cardiolipin and between NLRP3 and NEK7, a recently recognized component of the NLRP3 inflammasome needed for NLRP3 oligomerization. Protein transduction of cytochrome c impairs NLRP3 inflammasome activation, while partially silencing cytochrome c expression enhances it. The addition of cytochrome c to an in vitro inflammasome assay severely limited caspase-1 activation. We propose that there is a crosstalk between the NLRP3 inflammasome and apoptosome pathways mediated by cytochrome c, whose release during apoptosis acts to limit NLRP3 inflammasome activation.
authors.affiliation: B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Chong-Shan
authors.initials: CS
authors.lastname: Shi
authors.affiliation: B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: John H
authors.initials: JH
authors.lastname: Kehrl
mesh_terms: D017209:Apoptosis; D002308:Cardiolipins / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D000072379:NIMA-Related Kinases / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*
chemical_list: D002308:Cardiolipins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D045304:Cytochromes c; C512685:NEK7 protein, human; D000072379:NIMA-Related Kinases