CARD-only proteins regulate in vivo inflammasome responses and ameliorate gout
Savita Devi,
Mohanalaxmi Indramohan,
Elisabeth Jäger,
Jessica Carriere,
Lan H. Chu,
Lucia de Almeida,
David R. Greaves,
Christian Stehlik,
Andrea Dorfleutner
Affiliations
Savita Devi
Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
Mohanalaxmi Indramohan
Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
Elisabeth Jäger
Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
Jessica Carriere
Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
Lan H. Chu
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Driskill Graduate Program in Life Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Lucia de Almeida
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
David R. Greaves
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
Christian Stehlik
Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; The Kao Autoimmunity Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Corresponding author
Andrea Dorfleutner
Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; The Kao Autoimmunity Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Corresponding author
Summary: 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.
