NEK7磷酸化可放大NLRP3炎性体在钾外排和气真皮蛋白D下游的激活

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2025-01-03 DOI:10.1126/sciimmunol.adl2993

Jie Xu, Lingzhi Zhang, Yanhui Duan, Fangyuan Sun, Nouha Odeh, Yuan He, Gabriel Núñez

{"title":"NEK7磷酸化可放大NLRP3炎性体在钾外排和气真皮蛋白D下游的激活","authors":"Jie Xu, Lingzhi Zhang, Yanhui Duan, Fangyuan Sun, Nouha Odeh, Yuan He, Gabriel Núñez","doi":"10.1126/sciimmunol.adl2993","DOIUrl":null,"url":null,"abstract":"<div >The NLRP3 inflammasome plays a critical role in innate immunity and inflammatory diseases. NIMA-related kinase 7 (NEK7) is essential for inflammasome activation, and its interaction with NLRP3 is enhanced by K+ efflux. However, the mechanism by which K+ efflux promotes this interaction remains unknown. Here, we show that NEK7 is rapidly phosphorylated at threonine-190/191 by JNK1 downstream of K+ efflux and gasdermin D (GSDMD) after NLRP3 activation. NEK7 phosphorylation enhances the binding between NEK7 and NLRP3, which further promotes inflammasome assembly and activation. Mutant mice and macrophages in which Thr190 and Thr191 of Nek7 were replaced by valine exhibited impaired NEK7 phosphorylation, NLRP3 inflammasome activation, and IL-1β secretion. Thus, NEK7 phosphorylation is an important event that acts downstream of K+ efflux and GSDMD to further enhance NLRP3 inflammasome activation.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6000,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"NEK7 phosphorylation amplifies NLRP3 inflammasome activation downstream of potassium efflux and gasdermin D\",\"authors\":\"Jie Xu, Lingzhi Zhang, Yanhui Duan, Fangyuan Sun, Nouha Odeh, Yuan He, Gabriel Núñez\",\"doi\":\"10.1126/sciimmunol.adl2993\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >The NLRP3 inflammasome plays a critical role in innate immunity and inflammatory diseases. NIMA-related kinase 7 (NEK7) is essential for inflammasome activation, and its interaction with NLRP3 is enhanced by K+ efflux. However, the mechanism by which K+ efflux promotes this interaction remains unknown. Here, we show that NEK7 is rapidly phosphorylated at threonine-190/191 by JNK1 downstream of K+ efflux and gasdermin D (GSDMD) after NLRP3 activation. NEK7 phosphorylation enhances the binding between NEK7 and NLRP3, which further promotes inflammasome assembly and activation. Mutant mice and macrophages in which Thr190 and Thr191 of Nek7 were replaced by valine exhibited impaired NEK7 phosphorylation, NLRP3 inflammasome activation, and IL-1β secretion. Thus, NEK7 phosphorylation is an important event that acts downstream of K+ efflux and GSDMD to further enhance NLRP3 inflammasome activation.</div>\",\"PeriodicalId\":21734,\"journal\":{\"name\":\"Science Immunology\",\"volume\":\"10 103\",\"pages\":\"\"},\"PeriodicalIF\":17.6000,\"publicationDate\":\"2025-01-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/sciimmunol.adl2993\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/sciimmunol.adl2993","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}

引用次数: 0

摘要

NLRP3炎症小体在先天免疫和炎症性疾病中起关键作用。nima相关激酶7 （NEK7）对炎性小体的激活至关重要，其与NLRP3的相互作用通过K +外排增强。然而，K +外溢促进这种相互作用的机制尚不清楚。在这里，我们发现NLRP3激活后，NEK7在苏氨酸-190/191位点被K +外排下游的JNK1和gasdermin D （GSDMD）快速磷酸化。NEK7磷酸化增强了NEK7与NLRP3之间的结合，从而进一步促进炎症小体的组装和激活。Nek7的Thr 190和Thr 191被缬氨酸取代的突变小鼠和巨噬细胞表现出Nek7磷酸化、NLRP3炎性体激活和IL-1β分泌受损。因此，NEK7磷酸化是一个重要的事件，它作用于K +外排和GSDMD下游，进一步增强NLRP3炎性体的激活。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

NEK7 phosphorylation amplifies NLRP3 inflammasome activation downstream of potassium efflux and gasdermin D

The NLRP3 inflammasome plays a critical role in innate immunity and inflammatory diseases. NIMA-related kinase 7 (NEK7) is essential for inflammasome activation, and its interaction with NLRP3 is enhanced by K⁺ efflux. However, the mechanism by which K⁺ efflux promotes this interaction remains unknown. Here, we show that NEK7 is rapidly phosphorylated at threonine-190/191 by JNK1 downstream of K⁺ efflux and gasdermin D (GSDMD) after NLRP3 activation. NEK7 phosphorylation enhances the binding between NEK7 and NLRP3, which further promotes inflammasome assembly and activation. Mutant mice and macrophages in which Thr¹⁹⁰ and Thr¹⁹¹ of Nek7 were replaced by valine exhibited impaired NEK7 phosphorylation, NLRP3 inflammasome activation, and IL-1β secretion. Thus, NEK7 phosphorylation is an important event that acts downstream of K⁺ efflux and GSDMD to further enhance NLRP3 inflammasome activation.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.