RRC ID 72014
Author Nishitani-Isa M, Mukai K, Honda Y, Nihira H, Tanaka T, Shibata H, Kodama K, Hiejima E, Izawa K, Kawasaki Y, Osawa M, Katata Y, Onodera S, Watanabe T, Uchida T, Kure S, Takita J, Ohara O, Saito MK, Nishikomori R, Taguchi T, Sasahara Y, Yasumi T.
Title Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation.
Journal J Exp Med
Abstract 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.
Volume 219(6)
Published 2022-6-6
DOI 10.1084/jem.20211889
PII 213184
PMID 35482294
PMC PMC9059393
MeSH Golgi Apparatus* / metabolism Humans Inflammasomes* / metabolism Pyrin / genetics Pyrin / metabolism
Resource
DNA material CSII-EF-RfA (RDB04387)