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Journal Article Ppublish 4 citations

PubMed: 42566498 DOI: 10.1126/sciimmunol.aea0515

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

Sci Immunol 11(122):eaea0515

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

Affiliations

  • Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Université Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France.
  • Sorbonne University, Department of Internal Medicine, Tenon Hospital, DMU3ID, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • French National Reference Center for Autoinflammatory Diseases (CEREMAIA), Paris, France.
  • ERN RITA European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Disease Network, Utrecht, Netherlands.
  • Pediatric Department, Versailles Hospital, Le Chesnay, France.
  • Fédération Hospitalo-Universitaire INFLAMME, Paris, France.
  • Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
  • Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
  • Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan.
  • Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
  • National Center for Rare Diseases, Istituto Superiore di Sanità, Rome, Italy.
  • Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Cité, CNRS, Paris, France.
  • Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Internal Medicine Unit, Tenon Hospital, Paris, France.
  • Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
  • CIRI, Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon 1, Inserm U1111, CNRS, UMR5308, ENS de Lyon, Lyon, France.
  • Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • Department of Clinical Genetics, Yokohama City University Hospital, Yokohama, Japan.
  • Service de Médecine Interne, Centre de Référence pour les Maladies auto immunes et auto inflammatoires Systémiques Rares d'Auvergne, CHU Gabriel-Montpied, Inserm U1071, M2iSH, USC-INRA 1382, Clermont-Ferrand, France, Université Clermont Auvergne, Clermont-Ferrand, France.
  • Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • Service de Médecine Interne, Groupe Hospitalier Diaconesses Croix St Simon, Paris, France.
  • Department of Medical Genetics, Osaka Women's and Children's Hospital, Osaka, Japan.
  • Graduate School, International University of Health and Welfare, Tokyo, Japan.
  • Department of Biological Sciences, Nagoya University, Nagoya, Japan.
  • Molecular Genetics and Functional Genomics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
  • Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center, Aichi, Japan.
  • Department of Neurochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Institut Imagine, INSERM U1163, CNRS ERL 8254, Université Paris Descartes, Sorbonne Paris-Cite, Laboratoire d'Excellence GR-Ex, Paris, France.
  • Medical Genome Center, National Center for Neurology and Psychiatry, Kodaira, Japan.
  • Department of Molecular Genetics and Cytogenomics, Rare and Auto Inflammatory Diseases Unit, CHU Montpellier, University of Montpellier, Montpellier, France.
  • IRMB, INSERM U1183, Montpellier, France.
  • School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
  • Department of Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan.
  • Japan Environment and Children's Study (JECS) Kyoto Regional Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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.

MeSH

Pyrin, Inflammasomes, Gtp Phosphohydrolases

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