• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

CDC42 羧基末端变异体在高尔基体中的捕获导致 pyrin 炎性小体过度激活。

Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation.

机构信息

Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.

出版信息

J Exp Med. 2022 Jun 6;219(6). doi: 10.1084/jem.20211889. Epub 2022 Apr 28.

DOI:10.1084/jem.20211889
PMID:35482294
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9059393/
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 CDC42192C24 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.

摘要

CDC42 基因 C 末端区域的突变可导致严重的新生儿起病的自身炎症。IL-1β 阻断治疗的有效性表明该病理学涉及异常的炎症小体激活；然而，自身炎症的机制仍有待阐明。我们使用从携带 CDC42R186C 的患者中建立的诱导多能干细胞发现，与对照细胞相比，患者来源的细胞在受到吡喃激活刺激时会分泌更多的 IL-1β。CDC42R186C 蛋白的异常棕榈酰化和向高尔基体的定位促进了 pyrin 炎症小体在 pyrin 去磷酸化的下游组装。异常的亚细胞定位是具有炎症表型的 CDC42 C 末端变体的共同病理特征，包括也定位于高尔基体的 CDC42192C24。此外，pyrin 炎症小体过度激活的程度与高尔基体中突变蛋白的积累程度平行，但与突变 GTPase 活性无关。这些结果揭示了 CDC42 亚细胞定位与 pyrin 炎症小体激活之间的意外关联，这可能为阐明 pyrin 炎症小体形成的机制铺平道路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/fe326b586189/JEM_20211889_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/5af3dfbba799/JEM_20211889_GA.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/fd5ace01e90c/JEM_20211889_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/002a0d2399ac/JEM_20211889_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/ad4fc571a12a/JEM_20211889_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/8f8f2f0968b2/JEM_20211889_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/63f288a9224d/JEM_20211889_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/192ff23f63d7/JEM_20211889_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/a6ce7eecc939/JEM_20211889_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/cfa06aff7789/JEM_20211889_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/8cf73907c221/JEM_20211889_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/bd36734234f4/JEM_20211889_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/82a646c5cb09/JEM_20211889_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/fe326b586189/JEM_20211889_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/5af3dfbba799/JEM_20211889_GA.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/fd5ace01e90c/JEM_20211889_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/002a0d2399ac/JEM_20211889_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/ad4fc571a12a/JEM_20211889_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/8f8f2f0968b2/JEM_20211889_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/63f288a9224d/JEM_20211889_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/192ff23f63d7/JEM_20211889_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/a6ce7eecc939/JEM_20211889_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/cfa06aff7789/JEM_20211889_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/8cf73907c221/JEM_20211889_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/bd36734234f4/JEM_20211889_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/82a646c5cb09/JEM_20211889_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9330/9059393/fe326b586189/JEM_20211889_FigS5.jpg

相似文献

1
Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation.CDC42 羧基末端变异体在高尔基体中的捕获导致 pyrin 炎性小体过度激活。
J Exp Med. 2022 Jun 6;219(6). doi: 10.1084/jem.20211889. Epub 2022 Apr 28.
2
CDC42 regulates PYRIN inflammasome assembly.CDC42 调控 PYRRIN 炎性小体组装。
Cell Rep. 2022 Nov 15;41(7):111636. doi: 10.1016/j.celrep.2022.111636.
3
Pyrin Inflammasome Activation Abrogates Interleukin-1 Receptor Antagonist, Suggesting a New Mechanism Underlying Familial Mediterranean Fever Pathogenesis.Pyrin 炎症小体的激活可阻断白细胞介素-1 受体拮抗剂，提示家族性地中海热发病机制的新机制。
Arthritis Rheumatol. 2021 Nov;73(11):2116-2126. doi: 10.1002/art.41770. Epub 2021 Sep 22.
4
Characterization of Pyrin Dephosphorylation and Inflammasome Activation in Macrophages as Triggered by the Effectors YopE and YopT.效应物 YopE 和 YopT 触发的巨噬细胞中 Pyrin 的去磷酸化和炎症小体激活的表征。
Infect Immun. 2019 Feb 21;87(3). doi: 10.1128/IAI.00822-18. Print 2019 Mar.
5
Familial Mediterranean fever mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome.家族性地中海热突变是超显性突变，可特异性降低吡啉炎性小体的激活阈值。
Rheumatology (Oxford). 2018 Jan 1;57(1):100-111. doi: 10.1093/rheumatology/kex373.
6
Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation.家族性地中海热突变解除了微管蛋白在吡啉炎性小体激活中的必要需求。
Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):14384-14389. doi: 10.1073/pnas.1613156113. Epub 2016 Nov 22.
7
HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation.HDAC6 通过类似聚集物的机制介导 NLRP3 和 pyrin 炎症小体的激活。
Science. 2020 Sep 18;369(6510). doi: 10.1126/science.aas8995.
8
Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS.自身炎症性疾病家族性地中海热（FMF）和高免疫球蛋白D综合征（HIDS）中的吡啉炎性小体激活和RhoA信号传导
Nat Immunol. 2016 Aug;17(8):914-21. doi: 10.1038/ni.3457. Epub 2016 Jun 6.
9
Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients.Pyrin 去磷酸化足以触发家族性地中海热患者的炎症小体激活。
EMBO Mol Med. 2019 Nov 7;11(11):e10547. doi: 10.15252/emmm.201910547. Epub 2019 Oct 7.
10
The Inflammasome Components NLRP3 and ASC Act in Concert with IRGM To Rearrange the Golgi Apparatus during Hepatitis C Virus Infection.炎症小体组件 NLRP3 和 ASC 与 IRGM 协同作用，在丙型肝炎病毒感染期间重排高尔基体。
J Virol. 2021 Jan 13;95(3). doi: 10.1128/JVI.00826-20.

引用本文的文献

1
Immune-related actinopathies at the cross-road of immunodeficiency, autoimmunity and autoinflammation.免疫缺陷、自身免疫和自身炎症交叉路口的免疫相关肌动蛋白病。
Nat Rev Immunol. 2025 Sep 10. doi: 10.1038/s41577-025-01214-w.
2
Autoinflammatory patients with Golgi-trapped CDC42 exhibit intracellular trafficking defects leading to STING hyperactivation and ER stress.高尔基滞留 CDC42 的自身炎症患者存在细胞内运输缺陷，导致 STING 过度激活和内质网应激。
Nat Commun. 2024 Nov 16;15(1):9940. doi: 10.1038/s41467-024-54294-y.
3
Inflammasome components as new therapeutic targets in inflammatory disease.

本文引用的文献

1
Rapid Flow Cytometry-Based Assay for the Functional Classification of MEFV Variants.基于快速流式细胞术的 MEFV 变异体功能分类检测方法。
J Clin Immunol. 2021 Aug;41(6):1187-1197. doi: 10.1007/s10875-021-01021-7. Epub 2021 Mar 17.
2
Elucidation of the Pathogenesis of Autoinflammatory Diseases Using iPS Cells.利用诱导多能干细胞阐明自身炎症性疾病的发病机制
Children (Basel). 2021 Feb 1;8(2):94. doi: 10.3390/children8020094.
3
Homeostatic regulation of STING by retrograde membrane traffic to the ER.通过逆行膜运输到内质网来调节 STING 的稳态。
炎症小体成分作为炎症性疾病的新治疗靶点。
Nat Rev Immunol. 2025 Jan;25(1):22-41. doi: 10.1038/s41577-024-01075-9. Epub 2024 Sep 9.
4
RAC2 gain-of-function variants causing inborn error of immunity drive NLRP3 inflammasome activation.RAC2 获得性功能变异导致先天性免疫错误驱动 NLRP3 炎性体激活。
J Exp Med. 2024 Oct 7;221(10). doi: 10.1084/jem.20231562. Epub 2024 Aug 30.
5
Human induced pluripotent stem cells (NIHTVBi029-A and NIHTVBi030-A) generated from two patients with a heterozygous mutation in the CDC42 gene.由两位携带 CDC42 基因突变的杂合子患者生成的人诱导多能干细胞（NIHTVBi029-A 和 NIHTVBi030-A）。
Stem Cell Res. 2024 Oct;80:103517. doi: 10.1016/j.scr.2024.103517. Epub 2024 Jul 30.
6
CircCDC42-encoded CDC42-165aa regulates macrophage pyroptosis in Klebsiella pneumoniae infection through Pyrin inflammasome activation.环状 CDC42 编码的 CDC42-165aa 通过 Pyrin 炎性小体激活调控肺炎克雷伯菌感染中的巨噬细胞焦亡
Nat Commun. 2024 Jul 8;15(1):5730. doi: 10.1038/s41467-024-50154-x.
7
Genetic Rare Variants Affecting Multiple Pathways in Japanese Patients with Palindromic Rheumatism.遗传罕见变异影响日本复发性风湿症患者的多个通路。
Kobe J Med Sci. 2024 Apr 30;70(1):E26-E38. doi: 10.24546/0100489391.
8
Interrupting an IFN-γ-dependent feedback loop in the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne.中断化脓性关节炎、坏疽性脓皮病和痤疮综合征中 IFN-γ 依赖性反馈环。
Ann Rheum Dis. 2024 May 15;83(6):787-798. doi: 10.1136/ard-2023-225085.
9
Cellular models in autoinflammatory disease research.自身炎症性疾病研究中的细胞模型。
Clin Transl Immunology. 2024 Jan 11;13(1):e1481. doi: 10.1002/cti2.1481. eCollection 2024.
10
Biological and clinical roles of IL-18 in inflammatory diseases.IL-18 在炎症性疾病中的生物学和临床作用。
Nat Rev Rheumatol. 2024 Jan;20(1):33-47. doi: 10.1038/s41584-023-01053-w. Epub 2023 Dec 11.
Nat Commun. 2021 Jan 4;12(1):61. doi: 10.1038/s41467-020-20234-9.
4
Monogenic autoinflammatory disorders: Conceptual overview, phenotype, and clinical approach.单基因自身炎症性疾病：概念概述、表型和临床方法。
J Allergy Clin Immunol. 2020 Nov;146(5):925-937. doi: 10.1016/j.jaci.2020.08.017.
5
The role of interleukin-18 in the diagnosis and monitoring of hemophagocytic lymphohistiocytosis/macrophage activation syndrome - a systematic review.白细胞介素-18 在噬血细胞性淋巴组织细胞增多症/巨噬细胞活化综合征诊断和监测中的作用——系统评价。
Clin Exp Immunol. 2021 Feb;203(2):174-182. doi: 10.1111/cei.13543. Epub 2020 Nov 23.
6
A toxic palmitoylation of Cdc42 enhances NF-κB signaling and drives a severe autoinflammatory syndrome.Cdc42的毒性棕榈酰化增强了NF-κB信号传导并引发严重的自身炎症综合征。
J Allergy Clin Immunol. 2020 Nov;146(5):1201-1204.e8. doi: 10.1016/j.jaci.2020.03.020. Epub 2020 Apr 10.
7
A Novel Mutation in an 11-Year Old Child Manifesting as Syndromic Immunodeficiency, Autoinflammation, Hemophagocytic Lymphohistiocytosis, and Malignancy: A Case Report.一例 11 岁患儿表现为综合征性免疫缺陷、自身炎症、噬血细胞性淋巴组织细胞增生症和恶性肿瘤的新型突变：病例报告。
Front Immunol. 2020 Mar 13;11:318. doi: 10.3389/fimmu.2020.00318. eCollection 2020.
8
Systemic Inflammation and Myelofibrosis in a Patient with Takenouchi-Kosaki Syndrome due to CDC42 Tyr64Cys Mutation.一名因CDC42 Tyr64Cys突变导致竹内-小崎综合征患者的全身炎症与骨髓纤维化
J Clin Immunol. 2020 May;40(4):567-570. doi: 10.1007/s10875-020-00742-5. Epub 2020 Jan 18.
9
A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function.一种新的疾病，涉及由于 CDC42 功能异常导致的血液系统异常、炎症和 HLH。
J Exp Med. 2019 Dec 2;216(12):2778-2799. doi: 10.1084/jem.20190147. Epub 2019 Oct 10.
10
Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients.Pyrin 去磷酸化足以触发家族性地中海热患者的炎症小体激活。
EMBO Mol Med. 2019 Nov 7;11(11):e10547. doi: 10.15252/emmm.201910547. Epub 2019 Oct 7.