蛋白分离酶VCP/p97通过调节SYK活化促进宿主的抗真菌防御。

IF 5.5 1区 医学 Q1 MICROBIOLOGY PLoS Pathogens Pub Date : 2024-10-29 eCollection Date: 2024-10-01 DOI:10.1371/journal.ppat.1012674
Zhugui Shao, Li Wang, Limin Cao, Tian Chen, Xin-Ming Jia, Wanwei Sun, Chengjiang Gao, Hui Xiao
{"title":"蛋白分离酶VCP/p97通过调节SYK活化促进宿主的抗真菌防御。","authors":"Zhugui Shao, Li Wang, Limin Cao, Tian Chen, Xin-Ming Jia, Wanwei Sun, Chengjiang Gao, Hui Xiao","doi":"10.1371/journal.ppat.1012674","DOIUrl":null,"url":null,"abstract":"<p><p>C-type lectin receptors (CLRs) are essential to execute host defense against fungal infection. Nevertheless, a comprehensive understanding of the molecular underpinnings of CLR signaling remains a work in progress. Here, we searched for yet-to-be-identified tyrosine-phosphorylated proteins in Dectin-1 signaling and linked the stress-response protein valosin containing protein (VCP)/p97 to Dectin-1 signaling. Knockdown of VCP expression or chemical inhibition of VCP's segregase activity dampened Dectin-1-elicited SYK activation in BMDMs and BMDCs, leading to attenuated expression of proinflammatory cytokines/chemokines such as TNF-α, IL-6 and CXCL1. Biochemical analyses demonstrated that VCP and its cofactor UFD1 form a complex with SYK and its phosphatase SHP-1 following Dectin-1 ligation, and knockdown of VCP led to a more prominent SYK and SHP-1 association. Further, SHP-1 became polyubiquitinated upon Dectin-1 activation, and VCP or UFD1 overexpression accelerated SHP-1 degradation. Conceivably, VCP may promote Dectin-1 signaling by pulling the ubiquitinated SHP-1 out of the SYK complex for degradation. Finally, genetic ablation of VCP in the neutrophil and macrophage compartment rendered the mice highly susceptible to infection by Candida albicans, an observation also phenocopied by administering the VCP inhibitor. These results collectively demonstrate that VCP is a previously unappreciated signal transducer of the Dectin-1 pathway and a crucial component of antifungal defense, and suggest a new mechanism regulating SYK activation.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012674"},"PeriodicalIF":5.5000,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11548748/pdf/","citationCount":"0","resultStr":"{\"title\":\"The protein segregase VCP/p97 promotes host antifungal defense via regulation of SYK activation.\",\"authors\":\"Zhugui Shao, Li Wang, Limin Cao, Tian Chen, Xin-Ming Jia, Wanwei Sun, Chengjiang Gao, Hui Xiao\",\"doi\":\"10.1371/journal.ppat.1012674\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>C-type lectin receptors (CLRs) are essential to execute host defense against fungal infection. Nevertheless, a comprehensive understanding of the molecular underpinnings of CLR signaling remains a work in progress. Here, we searched for yet-to-be-identified tyrosine-phosphorylated proteins in Dectin-1 signaling and linked the stress-response protein valosin containing protein (VCP)/p97 to Dectin-1 signaling. Knockdown of VCP expression or chemical inhibition of VCP's segregase activity dampened Dectin-1-elicited SYK activation in BMDMs and BMDCs, leading to attenuated expression of proinflammatory cytokines/chemokines such as TNF-α, IL-6 and CXCL1. Biochemical analyses demonstrated that VCP and its cofactor UFD1 form a complex with SYK and its phosphatase SHP-1 following Dectin-1 ligation, and knockdown of VCP led to a more prominent SYK and SHP-1 association. Further, SHP-1 became polyubiquitinated upon Dectin-1 activation, and VCP or UFD1 overexpression accelerated SHP-1 degradation. Conceivably, VCP may promote Dectin-1 signaling by pulling the ubiquitinated SHP-1 out of the SYK complex for degradation. Finally, genetic ablation of VCP in the neutrophil and macrophage compartment rendered the mice highly susceptible to infection by Candida albicans, an observation also phenocopied by administering the VCP inhibitor. These results collectively demonstrate that VCP is a previously unappreciated signal transducer of the Dectin-1 pathway and a crucial component of antifungal defense, and suggest a new mechanism regulating SYK activation.</p>\",\"PeriodicalId\":48999,\"journal\":{\"name\":\"PLoS Pathogens\",\"volume\":\"20 10\",\"pages\":\"e1012674\"},\"PeriodicalIF\":5.5000,\"publicationDate\":\"2024-10-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11548748/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"PLoS Pathogens\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1371/journal.ppat.1012674\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/10/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"PLoS Pathogens","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1371/journal.ppat.1012674","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

C型凝集素受体(CLR)对于宿主抵御真菌感染至关重要。然而,全面了解 CLR 信号转导的分子基础仍是一项正在进行的工作。在此,我们寻找了 Dectin-1 信号转导中尚未确定的酪氨酸磷酸化蛋白,并将应激反应蛋白含缬氨酸蛋白(VCP)/p97 与 Dectin-1 信号转导联系起来。敲除 VCP 的表达或化学抑制 VCP 的分离酶活性可抑制 Dectin-1 在 BMDMs 和 BMDCs 中引发的 SYK 激活,从而减少 TNF-α、IL-6 和 CXCL1 等促炎细胞因子/趋化因子的表达。生化分析表明,在 Dectin-1 连接后,VCP 及其辅助因子 UFD1 与 SYK 及其磷酸酶 SHP-1 形成复合物,而敲除 VCP 会导致 SYK 和 SHP-1 的关联更加突出。此外,SHP-1在Dectin-1激活后会被多泛素化,而VCP或UFD1的过表达会加速SHP-1的降解。可以想象,VCP可能通过将泛素化的SHP-1从SYK复合物中拉出降解来促进Dectin-1的信号转导。最后,基因消减中性粒细胞和巨噬细胞中的 VCP 会使小鼠极易受到白色念珠菌的感染,通过注射 VCP 抑制剂也能观察到这一现象。这些结果共同证明,VCP 是一种以前未被重视的 Dectin-1 通路信号转导子,也是抗真菌防御的一个重要组成部分,并提出了一种调节 SYK 激活的新机制。
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
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
The protein segregase VCP/p97 promotes host antifungal defense via regulation of SYK activation.

C-type lectin receptors (CLRs) are essential to execute host defense against fungal infection. Nevertheless, a comprehensive understanding of the molecular underpinnings of CLR signaling remains a work in progress. Here, we searched for yet-to-be-identified tyrosine-phosphorylated proteins in Dectin-1 signaling and linked the stress-response protein valosin containing protein (VCP)/p97 to Dectin-1 signaling. Knockdown of VCP expression or chemical inhibition of VCP's segregase activity dampened Dectin-1-elicited SYK activation in BMDMs and BMDCs, leading to attenuated expression of proinflammatory cytokines/chemokines such as TNF-α, IL-6 and CXCL1. Biochemical analyses demonstrated that VCP and its cofactor UFD1 form a complex with SYK and its phosphatase SHP-1 following Dectin-1 ligation, and knockdown of VCP led to a more prominent SYK and SHP-1 association. Further, SHP-1 became polyubiquitinated upon Dectin-1 activation, and VCP or UFD1 overexpression accelerated SHP-1 degradation. Conceivably, VCP may promote Dectin-1 signaling by pulling the ubiquitinated SHP-1 out of the SYK complex for degradation. Finally, genetic ablation of VCP in the neutrophil and macrophage compartment rendered the mice highly susceptible to infection by Candida albicans, an observation also phenocopied by administering the VCP inhibitor. These results collectively demonstrate that VCP is a previously unappreciated signal transducer of the Dectin-1 pathway and a crucial component of antifungal defense, and suggest a new mechanism regulating SYK 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
PLoS Pathogens
PLoS Pathogens MICROBIOLOGY-PARASITOLOGY
自引率
3.00%
发文量
598
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
期刊最新文献
Eimeria: Navigating complex intestinal ecosystems. Diclofenac sensitizes multi-drug resistant Acinetobacter baumannii to colistin. Massive entry of BK Polyomavirus induces transient cytoplasmic vacuolization of human renal proximal tubule epithelial cells. SARS-CoV-2 evolution balances conflicting roles of N protein phosphorylation. TMPRSS2 in microbial interactions: Insights from HKU1 and TcsH.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1