An autoinflammatory CDC42 variant M45L demonstrates the mechanism of pyrin inflammasome activation
Abstract
CDC42 is an evolutionarily conserved guanosine triphosphatase (GTPase) regulating critical cellular and immune processes. Variants in CDC42 therefore cause a spectrum of developmental phenotypes, including hematological and immunological symptoms. Here, we identify a previously unrecognized autoinflammatory condition caused by CDC42 Met45→Leu(M45L) . We confirm the pathogenicity of CDC42 M45L given that it promotes pyrin inflammasome activation, consistent with highly elevated circulating interleukin-18 (IL-18) in all affected individuals. Coimmunoprecipitation demonstrates that CDC42 interacts with the PYD and B30.2 domains of pyrin. The B30.2 interaction is greatly enhanced by CDC42 M45L . Models show that CDC42 methionine-45 sits in a hydrophobic cleft of the pyrin B30.2 domain, and substitution with a negatively charged residue prevents colocalization between CDC42 and pyrin. This study supports a model whereby CDC42 nucleates pyrin via the B30.2 domain, after which a threshold is reached to liberate the PYD for inflammasome activation. Blocking the inflammasome-associated cytokine IL-1 was therapeutically effective when tested against this autoinflammatory CDC42 M45L endotype.
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Authors: Shouya Feng, Thomas Reygaerts, Klara Kong, Matthew C Wierzbowski, Dhanya Lakshmi Narayanan, Paul J. Baker, Imogen Bishop, Maria Zyulina, Katherine Rosevear, Madeline L. Cleveland, Tim Hewitt, T. Daniel Andrews, Davide Randazzo, Peter Steinbach, Jae Jin Chae, Hyeonji Kim, Daniel L. Kastner, William D Renton, Samar Ojaimi, Wonyong Lee, Seth L. Masters
Institutions: The University of Melbourne, Monash University, Australian National University, University of Bonn, Monash Health, Royal Children's Hospital, National Institutes of Health, Hudson Institute of Medical Research, Walter and Eliza Hall Institute of Medical Research, Hallym University, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, Institute for Basic Science, Monash Children’s Hospital