Aberrant localization of CDC42 C-terminal variants to the Golgi apparatus drives pyrin inflammasome-dependent autoinflammation
Aberrant localization of CDC42 C-terminal variants to the Golgi apparatus drives pyrin inflammasome-dependent autoinflammation
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CDC42 C 末端变体在高尔基体的异常定位驱动吡啶炎症小体依赖性自身炎症
DOI：
10.1101/2021.09.03.458902
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
T.
中科院分区：
文献类型：
--
作者：
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.;Kure;S.;Takita;J.;Ohara;O.;Saito;M. K.;Nishikomori;R.;Taguchi;T.
cddc42基因c端区域的突变可导致新生儿发生严重的自身炎症。患者血清IL-18水平升高和il -1β阻断治疗的有效性表明病理涉及异常炎性体活化；然而，自身炎症的机制仍有待阐明。使用从携带cdc42r186c的患者身上建立的诱导多能干细胞，我们发现患者来源的细胞在响应pyrin激活刺激时分泌更多的IL-1β。异常棕榈酰化和cdc42r186c蛋白在高尔基体上的定位促进了pyrin去磷酸化下游的pyrin炎性体组装。异常亚细胞定位是具有炎症表型的CDC42 c端变异的共同病理特征，包括CDC42*192C*24也定位于高尔基体。此外，pyrin炎性体的过度激活水平与高尔基体中突变蛋白的积累水平相似，但与突变GTPase活性无关。这些结果揭示了CDC42亚细胞定位与pyrin炎性小体激活之间的意外关联，为阐明pyrin炎性小体的形成机制铺平了道路。
Mutations in the C-terminal region of theCDC42gene cause severe neonatal-onset autoinflammation. Elevated levels of serum IL-18 in patients and effectiveness of IL-1β-blocking therapy indicate that the pathology involves abnormal inflammasome activation; however, the mechanism underlying autoinflammation remains to be elucidated. Using induced-pluripotent stem cells established from patients carryingCDC42R186C, we found that patient-derived cells secreted larger amounts of IL-1β in response to pyrin-activating stimuli. Aberrant palmitoylation and localization of CDC42R186Cprotein 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*24that also localizes to the Golgi apparatus. Furthermore, the level of pyrin inflammasome overactivation paralleled that of mutant protein accumulation in the Golgi apparatus, but no that of the mutant GTPase activity. These results reveal an unexpected association between CDC42 subcellular localization and pyrin inflammasome activation that could pave way for elucidating the mechanism of pyrin inflammasome formation.
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影响因子：
64.8
作者：
Komor AC;Kim YB;Packer MS;Zuris JA;Liu DR
通讯作者：
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影响因子：
2
作者：
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影响因子：
2
作者：
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DOI：
--
发表时间：
2007
期刊：
Blood 109
影响因子：
--
作者：
Fujisawa A;Kambe N;et al.
通讯作者：
et al.
影响因子：
15.3
作者：
Lam, Michael T.;Coppola, Simona;Tartaglia, Marco
通讯作者：
Tartaglia, Marco