TY - JOUR
T1 - Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation
AU - Nishitani-Isa, Masahiko
AU - Mukai, Kojiro
AU - Honda, Yoshitaka
AU - Nihira, Hiroshi
AU - Tanaka, Takayuki
AU - Shibata, Hirofumi
AU - Kodama, Kumi
AU - Hiejima, Eitaro
AU - Izawa, Kazushi
AU - Kawasaki, Yuri
AU - Osawa, Mitsujiro
AU - Katata, Yu
AU - Onodera, Sachiko
AU - Watanabe, Tatsuya
AU - Uchida, Takashi
AU - Kure, Shigeo
AU - Takita, Junko
AU - Ohara, Osamu
AU - Saito, Megumu K.
AU - Nishikomori, Ryuta
AU - Taguchi, Tomohiko
AU - Sasahara, Yoji
AU - Yasumi, Takahiro
N1 - Funding Information:
The authors are grateful to the patients and their families. This work was supported by JSPS KAKENHI (grant numbers 21K07795, 20H03202, and 19H00974), AMED (grant numbers JP20ek0109387, JP21bm0104001, JP21bm0804005, JP19bm0804001, and JP20gm5910025), the “Research on Measures for Intractable Diseases” project from the Japanese Ministry of Health, Labour and Welfare, and by the Mochida Memorial Foundation for Medical and Pharmaceutical Research.
Publisher Copyright:
© 2022 Nishitani-Isa et al.
PY - 2022/6/6
Y1 - 2022/6/6
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20211889
DO - 10.1084/jem.20211889
M3 - Article
C2 - 35482294
AN - SCOPUS:85129780516
SN - 0022-1007
VL - 219
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 6
M1 - e20211889
ER -