CARD-only proteins regulate in vivo inflammasome responses and ameliorate gout

• Published in: Cell reports (Cambridge) 2023-03, Vol.42 (3), p.112265-112265, Article 112265
• Main Authors: Devi, Savita, Indramohan, Mohanalaxmi, Jäger, Elisabeth, Carriere, Jessica, Chu, Lan H., de Almeida, Lucia, Greaves, David R., Stehlik, Christian, Dorfleutner, Andrea
• Format: Article
• Language: English
• Subjects: Animals; ASC; CARD; CARD Signaling Adaptor Proteins - metabolism; Caspase 1 - metabolism; caspase recruitment domain; caspase-1; COP; CP: Immunology; CP: Molecular biology; Gout; IL-1; inflammasome; Inflammasomes - metabolism; Inflammation - metabolism; interleukin-1; Interleukin-1beta - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112265

Inflammatory responses are crucial for controlling infections and initiating tissue repair. However, excessive and uncontrolled inflammation causes inflammatory disease. Processing and release of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 depend on caspase-1 activation within inflammasomes. Assembly of inflammasomes is initiated upon activation of cytosolic pattern recognition receptors (PRRs), followed by sequential polymerization of pyrin domain (PYD)-containing and caspase recruitment domain (CARD)-containing proteins mediated by homotypic PYD and CARD interactions. Small PYD- or CARD-only proteins (POPs and COPs, respectively) evolved in higher primates to target these crucial interactions to limit inflammation. Here, we show the ability of COPs to regulate inflammasome activation by modulating homotypic CARD-CARD interactions in vitro and in vivo. CARD16, CARD17, and CARD18 displace crucial CARD interactions between caspase-1 proteins through competitive binding and ameliorate uric acid crystal-mediated NLRP3 inflammasome activation and inflammatory disease. COPs therefore represent an important family of inflammasome regulators and ameliorate inflammatory disease. [Display omitted] •Caspase recruitment domain (CARD)-only proteins (COPs) regulate caspase-1 recruitment to the inflammasome•COPs inhibit caspase-1 activation•COPs inhibit caspase-1-mediated IL-1β and IL-18 release and prevent pyroptosis•COP transgenic mice are protected from inflammatory disease Devi et al. show that the three human caspase recruitment domain (CARD)-only proteins (COPs), CARD16, CARD17, and CARD18, prevent inflammasome assembly. COPs bind to the CARDs of ASC and caspase-1, thereby preventing caspase-1 activation, IL-1β and IL-18 release, and pyroptosis. COP transgenic mice exhibit ameliorated NLRP3 inflammasome-dependent inflammatory disease.