title: Cellular inhibitors of apoptosis proteins cIAP1 and cIAP2 are required for efficient caspase-1 activation by the inflammasome.
abstract: Pathogen and danger recognition by the inflammasome activates inflammatory caspases that mediate inflammation and cell death. The cellular inhibitor of apoptosis proteins (cIAPs) function in apoptosis and innate immunity, but their role in modulating the inflammasome and the inflammatory caspases is unknown. Here we report that the cIAPs are critical effectors of the inflammasome and are required for efficient caspase-1 activation. cIAP1, cIAP2, and the adaptor protein TRAF2 interacted with caspase-1-containing complexes and mediated the activating nondegradative K63-linked polyubiquitination of caspase-1. Deficiency in cIAP1 (encoded by Birc2) or cIAP2 (Birc3) impaired caspase-1 activation after spontaneous or agonist-induced inflammasome assembly, and Birc2(-/-) or Birc3(-/-) mice or mice administered with an IAP antagonist had a dampened response to inflammasome agonists and were resistant to peritonitis. Our results describe a role for the cIAPs in innate immunity and further demonstrate the evolutionary conservation between cell death and inflammation mechanisms.
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3G 0B1, Canada.
authors.forename: Katherine
authors.initials: K
authors.lastname: Labbé
authors.forename: Christian R
authors.initials: CR
authors.lastname: McIntire
authors.forename: Karine
authors.initials: K
authors.lastname: Doiron
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Leblanc
authors.forename: Maya
authors.initials: M
authors.lastname: Saleh
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D054875:Ubiquitination
chemical_list: D058847:Inflammasomes; D051034:Inhibitor of Apoptosis Proteins; D020170:Caspase 1