2026-08-08 京都大学高等研究院
＜関連情報＞
- https://ashbi.kyoto-u.ac.jp/ja/news_research/23367/
- https://www.science.org/doi/10.1126/sciimmunol.aea0515
- https://www.science.org/doi/10.1126/sciimmunol.aea0705
CDC42のN末端T43I変異体は、ピリンインフラマソーム活性化のメカニズムを明らかにする An N-terminal CDC42 T43I variant reveals the mechanism of pyrin inflammasome activation
Mariko Aoki, Alberto Iannuzzo, Philippe Mertz, Shouya Feng, […] , and Jérôme Delon
Science Immunology Published:7 Aug 2026
DOI:https://doi.org/10.1126/sciimmunol.aea0515
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 (Thr43→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.
遺伝子型優先アプローチにより、ピリンインフラマソーム活性化の分子基盤が明らかになる A genotype-first approach reveals the molecular basis of pyrin inflammasome activation
Naoya Iwata, Yoshihiko Kuchitsu, Atsushi Hijikata, Hirofumi Shibata, […] , and Yoshitaka Honda
Science Immunology Published:7 Aug 2026
DOI:https://doi.org/10.1126/sciimmunol.aea0705
Abstract
Mutations in the MEFV gene, which encodes pyrin, are associated with a spectrum of inflammatory conditions called pyrin-associated autoinflammatory diseases (PAADs). Of the 400 MEFV variants listed in the Infevers database, most are classified as variants of uncertain significance. Thus, genetic diagnosis of PAADs remains challenging, and the molecular mechanisms underlying pyrin activation remain poorly understood. Here, we used a cell-based pyroptosis assay to stratify 265 missense MEFV variants and identified previously uncharacterized pathogenic variants. We then characterized the interaction between the pyrin B30.2 domain and CDC42, a key regulator of pyrin intracellular trafficking and activation. We found that classical familial Mediterranean fever (FMF)–related variants bind tightly to CDC42 to induce pyrin hyperactivation, whereas certain non-FMF variants induce pyrin hyperactivation independently of CDC42, indicating involvement of multiple pathways in pyrin activation. Our approach provides a proof of concept for a genotype-first approach, which may advance our understanding of complex human diseases.
