Mutations in the C-terminal region of the CDC42 gene cause severe neonatal-onset autoinflammation. Effectiveness of IL-1β–blocking therapy indicates that the pathology involves abnormal inflammasome activation; however, the mechanism underlying autoinflammation remains to be elucidated. Using induced-pluripotent stem cells established from patients carrying CDC42R186C, we found that patient-derived cells secreted larger amounts of IL-1β in response to pyrin-activating stimuli. Aberrant palmitoylation and localization of CDC42R186C protein to the Golgi apparatus promoted pyrin inflammasome assembly downstream of pyrin dephosphorylation. Aberrant subcellular localization was the common pathological feature shared by CDC42 C-terminal variants with inflammatory phenotypes, including CDC42*192C*24 that also localizes to the Golgi apparatus. Furthermore, the level of pyrin inflammasome overactivation paralleled that of mutant protein accumulation in the Golgi apparatus, but not that of the mutant GTPase activity. These results reveal an unexpected association between CDC42 subcellular localization and pyrin inflammasome activation that could pave the way for elucidating the mechanism of pyrin inflammasome formation.
Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation
Disclosures: The authors declare no competing interests exist.
- Award Id(s): 21K07795,20H03202,19H00974
- Award Id(s): JP20ek0109387,JP21bm0104001,JP21bm0804005,JP19bm0804001,JP20gm5910025
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Masahiko Nishitani-Isa, Kojiro Mukai, Yoshitaka Honda, Hiroshi Nihira, Takayuki Tanaka, Hirofumi Shibata, Kumi Kodama, Eitaro Hiejima, Kazushi Izawa, Yuri Kawasaki, Mitsujiro Osawa, Yu Katata, Sachiko Onodera, Tatsuya Watanabe, Takashi Uchida, Shigeo Kure, Junko Takita, Osamu Ohara, Megumu K. Saito, Ryuta Nishikomori, Tomohiko Taguchi, Yoji Sasahara, Takahiro Yasumi; Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation. J Exp Med 6 June 2022; 219 (6): e20211889. doi: https://doi.org/10.1084/jem.20211889
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