title: Inhibiting the inflammasome: one domain at a time.
abstract: Inflammasomes are protein complexes that promote the maturation and release of pro-inflammatory cytokines and danger signals as well as pyroptosis in response to infections and cellular stress. Inflammasomes consist of a sensor, an adapter, and the effector caspase-1, which interact through homotypic interactions of caspase recruitment domains (CARDs) or PYRIN domains (PYDs). Hence, decoy proteins encoding only a CARD or PYD, COPs and POPs, respectively, are assumed to inhibit inflammasome assembly. Sensors encoding a PYD belong to the families of NOD-like receptors containing a PYD (NLRPs) or AIM2-like receptors (ALRs), which interact with the PYD- and CARD-containing adapter ASC through homotypic PYD interactions. Subsequently, ASC undergoes PYD-dependent oligomerization, which promotes CARD-mediated interactions between ASC and caspase-1, resulting in caspase-1 activation. POPs are suggested to interfere with the interaction between NLRPs/ALRs and ASC to prevent nucleation of ASC and therefore prevent an oligomeric platform for caspase-1 activation. Similarly, COPs are suggested to bind to the CARD of caspase-1 to prevent its recruitment to the oligomeric ASC platform and its activation. Alternatively, the adapter ASC may regulate inflammasome activity by expressing different isoforms, which are either capable or incapable of assembling an oligomeric ASC platform. The molecular mechanism of inflammasome assembly has only recently been elucidated, but the effects of most COPs and POPs on inflammasome assembly have not been investigated. Here, we discuss our model of COP- and POP-mediated inflammasome regulation.
authors: Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors: Andrea
authors: A
authors: Dorfleutner
authors: Lan
authors: L
authors: Chu
authors: Christian
authors: C
authors: Stehlik
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D000071198:Pyrin
chemical_list: D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; C436144:LLID-114769 protein, human; C000604192:MEFV protein, human; D046912:Multiprotein Complexes; C402202:PYCARD protein, human; D020033:Protein Isoforms; D000071198:Pyrin
keywords: ASC; CARD-only proteins (COPs); PYD-only proteins (POPs); caspase recruitment domain (CARD); inflammasome; pyrin domain (PYD)