An N-terminal CDC42 T43I variant reveals the mechanism of pyrin inflammasome activation

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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Publication Details

Journal
Science Immunology
Published
2026-08-07
DOI
https://doi.org/10.1126/sciimmunol.aea0515
Citations
3
Primary Topic
Inflammasome and immune disorders
Type
article
Field-Weighted Citation Impact
10.78

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article

An N-terminal CDC42 T43I variant reveals the mechanism of pyrin inflammasome activation

Yoshihiko Kuchitsu, Seth L. Masters, Nobuhiko Okamoto, Masahiko Nishitani‐Isa et al.
3 citations
Science Immunology
Inflammasome and immune disorders
10.78
article

An N-terminal CDC42 T43I variant reveals the mechanism of pyrin inflammasome activation

Yoshihiko Kuchitsu, Seth L. Masters, Nobuhiko Okamoto, Masahiko Nishitani‐Isa, Sarah Dalmon, Satoko Miyatake, Tomohiko Taguchi, Philippe Mertz, Kenichi Nishimura, Margaux Cescato, Megumu K. Saito, Asma Smahi, Guilaine Boursier, Takahiro Yasumi, Masashi Nishikawa, Shouya Feng, Atsushi Hijikata, Koh‐ichi Nagata, Marco Tartaglia, Rachida Tacine, Flora Magnotti, Véronique Hentgen, Chiara Perugini, Kazuhiro Ogata, Erika Zara, Jonathan London, Mathieu Paul Rodero, Akira Niwa, Yoshitaka Honda, Shuichi Ito, Kazushi Izawa, Yuri Kawasaki, Alexandre Terré, Naomi Tsuchida, Thomas Henry, Jérôme Delon, Junko Takita, Simona Coppola, Naomichi Matsumoto, Hirofumi Shibata, Alberto Iannuzzo, Keisuke Hamada, Marc André, Mariko Aoki, Laurent Le Corre, Naoya Iwata, Sophie Georgin-Lavialle, Rana El Masri
article en
3 citations

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.

Science ImmunologyVol. 11(122)
Université Claude Bernard Lyon 1 (FR), Délégation Paris 5 (FR), École Normale Supérieure de Lyon (FR), Centre National de la Recherche Scientifique (FR), Tokyo University of Pharmacy and Life Sciences (JP), Inserm (FR), The University of Melbourne (AU), University of Cologne (DE), Walter and Eliza Hall Institute of Medical Research (AU), Université de Montpellier (FR), Tohoku University (JP), Kyoto Women's University (JP), Université Paris Cité (FR), Kyoto University (JP), Istituto Superiore di Sanità (IT), Hudson Institute of Medical Research (AU), Sorbonne Université (FR), Osaka Women's and Children's Hospital (JP), Institute for Regenerative Medicine & Biotherapy (FR), Assistance Publique – Hôpitaux de Paris (FR), Yokohama City University Hospital (JP), Centre de Référence des Maladies Autoinflammatoires et des Amyloses (FR), National Center of Neurology and Psychiatry (JP), Fédération Hospitalo-Universitaire, Paris Center for Microbiome Medicine (FR), Groupe Hospitalier Diaconesses Croix Saint-Simon (FR), Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (FR), Bambino Gesù Children's Hospital (IT), Centre Hospitalier Universitaire de Clermont-Ferrand (FR), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Institut Cochin (FR), ERN GUARD-Heart (NL), Clermont Université (FR), Centre Hospitalier de Versailles (FR), Centre International de Recherche en Infectiologie (FR), Aichi Developmental Disability Center (JP), Hôpital Tenon (FR), Center for iPS Cell Research and Application, Kyoto University (JP), Monash University (AU), Nagoya University (JP), International University of Health and Welfare (JP), Yokohama City University (JP)
Japan Agency for Medical Research and Development, Agence Nationale de la Recherche, Fondation pour la Recherche Médicale, Ministero della Salute, Istituto Superiore di Sanità, National Health and Medical Research Council, Japan Society for the Promotion of Science, Japan Science and Technology Agency
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Openalex Percentile: Top 1%
Inflammasome and immune disorders
10.78
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