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Immunol."],"published-print":{"date-parts":[[2026,8,7]]},"abstract":"<jats:p>\n                    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\n                    <jats:sup>Met45\u2192Leu(M45L)<\/jats:sup>\n                    . We confirm the pathogenicity of CDC42\n                    <jats:sup>M45L<\/jats:sup>\n                    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\n                    <jats:sup>M45L<\/jats:sup>\n                    . 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\n                    <jats:sup>M45L<\/jats:sup>\n                    endotype.\n                  <\/jats:p>","DOI":"10.1126\/sciimmunol.adz8733","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:58:34Z","timestamp":1786125514000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":4,"title":["An autoinflammatory CDC42 variant M45L demonstrates the mechanism of pyrin inflammasome activation"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3529-3822","authenticated-orcid":true,"given":"Shouya","family":"Feng","sequence":"first","affiliation":[{"name":"Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia."},{"name":"Department of Molecular and Translational Science, 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