title: Intracellular sensing of complement C3 activates cell autonomous immunity.
abstract: Pathogens traverse multiple barriers during infection, including cell membranes. We found that during this transition, pathogens carried covalently attached complement C3 into the cell, triggering immediate signaling and effector responses. Sensing of C3 in the cytosol activated mitochondrial antiviral signaling (MAVS)-dependent signaling cascades and induced proinflammatory cytokine secretion. C3 also flagged viruses for rapid proteasomal degradation, preventing their replication. This system could detect both viral and bacterial pathogens but was antagonized by enteroviruses, such as rhinovirus and poliovirus, which cleave C3 using their 3C protease. The antiviral rupintrivir inhibited 3C protease and prevented C3 cleavage, rendering enteroviruses susceptible to intracellular complement sensing. Thus, complement C3 allows cells to detect and disable pathogens that have invaded the cytosol.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Jerry C H
authors.initials: JC
authors.lastname: Tam
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Susanna R
authors.initials: SR
authors.lastname: Bidgood
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: William A
authors.initials: WA
authors.lastname: McEwan
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. lcj@mrc-lmb.cam.ac.uk.
authors.forename: Leo C
authors.initials: LC
authors.lastname: James
mesh_terms: D000256:Adenoviridae / Q000276:immunology*; D000258:Adenovirus Infections, Human / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D003176:Complement C3 / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004285:Dogs; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D050835:Interferon Regulatory Factors / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D000099207:SS-A Antigen
chemical_list: D000914:Antibodies, Viral; D003176:Complement C3; D016207:Cytokines; D050835:Interferon Regulatory Factors; D016328:NF-kappa B; D046988:Proteasome Endopeptidase Complex; D012261:Ribonucleoproteins; D018808:Transcription Factor AP-1; D000099207:SS-A Antigen