An N-terminal CDC42 T43I variant reveals the mechanism of pyrin inflammasome activation
Abstract
Heterozygous carboxyl-terminal variants in the RHO guanosine triphosphatase (GTPase) CDC42 are known to cause severe autoinflammatory syndromes. Here, we identified a heterozygous amino-terminal p.T43I (Thr 43 →Ile) CDC42 variant in patients with autoinflammation and uncovered a molecular link between CDC42 and the inflammasome sensor pyrin, mutated in the hereditary autoinflammatory syndrome familial Mediterranean fever. We demonstrate that the region surrounding residue T43 of CDC42 interacts with the carboxyl-terminal B30.2 domain of pyrin and regulates its localization and activation. The p.T43I substitution strengthens the CDC42-pyrin interaction through additional van der Waals interactions, leading to increased pyrin inflammasome activation, as evidenced by increased ASC (apoptosis-associated speck-like protein containing a caspase activating and recruitment domain) speck formation, enhanced pyroptosis, and excessive interleukin-1β (IL-1β) and IL-18 production. These findings identify CDC42 as a pyrin ligand and provide critical insights into the role of the pyrin B30.2 domain in inflammasome activation, suggesting dual regulation of pyrin by two RHO family GTPases, RHOA and CDC42.
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Authors: Mariko Aoki, Alberto Iannuzzo, Philippe Mertz, Shouya Feng, Naoya Iwata, Chiara Perugini, Naomi Tsuchida, Rana El Masri, Yoshihiko Kuchitsu, Rachida Tacine, Simona Coppola, Hirofumi Shibata, Margaux Cescato, Masahiko Nishitani‐Isa, Alexandre Terré, Yuri Kawasaki, Sarah Dalmon, Kenichi Nishimura, Flora Magnotti, Satoko Miyatake, Marc André, Keisuke Hamada, Jonathan London, Kazushi Izawa, Akira Niwa, Nobuhiko Okamoto, Kazuhiro Ogata, Masashi Nishikawa, Erika Zara, Megumu K. Saito, Marco Tartaglia, Shuichi Ito, Mathieu P. Rodero, Koh‐ichi Nagata, Asma Smahi, Naomichi Matsumoto, Laurent Le Corre, Junko Takita, Guilaine Boursier, Atsushi Hijikata, Thomas Henry, Tomohiko Taguchi, Véronique Hentgen, Sophie Georgin-Lavialle, Yoshitaka Honda, Seth L. Masters, Takahiro Yasumi, Jérôme Delon
Institutions: The University of Melbourne, Kyoto University, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Inserm, Monash University, Yokohama City University, Université Paris Cité, Sorbonne Université, Délégation Paris 5, Centre National de la Recherche Scientifique, Tohoku University, Assistance Publique – Hôpitaux de Paris, Nagoya University, Lyon 1 Université, École Normale Supérieure de Lyon, Fédération Hospitalo-Universitaire, Paris Center for Microbiome Medicine, Hudson Institute of Medical Research, Université de Montpellier, Walter and Eliza Hall Institute of Medical Research, International University of Health and Welfare, Bambino Gesù Children's Hospital, Tokyo University of Pharmacy and Life Sciences, Kyoto Women's University, Institut Cochin, Centre de Référence des Maladies Autoinflammatoires et des Amyloses, ERN GUARD-Heart, Centre Hospitalier de Versailles, Hôpital Tenon, Yokohama City University Hospital, Istituto Superiore di Sanità, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Center for iPS Cell Research and Application, Kyoto University, Centre International de Recherche en Infectiologie, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont Université, Groupe Hospitalier Diaconesses Croix Saint-Simon, Osaka Women's and Children's Hospital, Aichi Developmental Disability Center, National Center of Neurology and Psychiatry, Institute for Regenerative Medicine & Biotherapy