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TcpC 通过作为 E3 泛素连接酶促进髓样分化因子 88 的降解来抑制 Toll 样受体信号通路。

TcpC inhibits toll-like receptor signaling pathway by serving as an E3 ubiquitin ligase that promotes degradation of myeloid differentiation factor 88.

机构信息

Institute of Translational Medicine, Zhejiang University City College, Hangzhou, Peoples Republic of China.

Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, Peoples Republic of China.

出版信息

PLoS Pathog. 2021 Mar 31;17(3):e1009481. doi: 10.1371/journal.ppat.1009481. eCollection 2021 Mar.

DOI:10.1371/journal.ppat.1009481
PMID:33788895
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8041205/
Abstract

TcpC is a virulence factor of uropathogenic E. coli (UPEC). It was found that TIR domain of TcpC impedes TLR signaling by direct association with MyD88. It has been a long-standing question whether bacterial pathogens have evolved a mechanism to manipulate MyD88 degradation by ubiquitin-proteasome pathway. Here, we show that TcpC is a MyD88-targeted E3 ubiquitin ligase. Kidney macrophages from mice with pyelonephritis induced by TcpC-secreting UPEC showed significantly decreased MyD88 protein levels. Recombinant TcpC (rTcpC) dose-dependently inhibited protein but not mRNA levels of MyD88 in macrophages. Moreover, rTcpC significantly promoted MyD88 ubiquitination and accumulation in proteasomes in macrophages. Cys12 and Trp106 in TcpC are crucial amino acids in maintaining its E3 activity. Therefore, TcpC blocks TLR signaling pathway by degradation of MyD88 through ubiquitin-proteasome system. Our findings provide not only a novel biochemical mechanism underlying TcpC-medicated immune evasion, but also the first example that bacterial pathogens inhibit MyD88-mediated signaling pathway by virulence factors that function as E3 ubiquitin ligase.

摘要

TcpC 是尿路致病性大肠杆菌 (UPEC) 的一种毒力因子。研究发现，TcpC 的 TIR 结构域通过与 MyD88 的直接结合来阻碍 TLR 信号通路。细菌病原体是否进化出一种通过泛素蛋白酶体途径来操纵 MyD88 降解的机制，这一直是一个悬而未决的问题。在这里，我们表明 TcpC 是一种 MyD88 靶向的 E3 泛素连接酶。由分泌 TcpC 的 UPEC 引起肾盂肾炎的小鼠的肾脏巨噬细胞中，MyD88 蛋白水平显著降低。重组 TcpC（rTcpC）以剂量依赖的方式抑制巨噬细胞中 MyD88 的蛋白而不是 mRNA 水平。此外，rTcpC 显著促进了巨噬细胞中 MyD88 的泛素化和在蛋白酶体中的积累。TcpC 中的 Cys12 和 Trp106 是维持其 E3 活性的关键氨基酸。因此，TcpC 通过泛素蛋白酶体系统降解 MyD88 来阻断 TLR 信号通路。我们的研究结果不仅提供了 TcpC 介导的免疫逃避的新的生化机制，而且还首次证明了细菌病原体通过作为 E3 泛素连接酶的毒力因子来抑制 MyD88 介导的信号通路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/fa5cf5f3ca13/ppat.1009481.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/0d1ca08e521e/ppat.1009481.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/d96a3ef06aa6/ppat.1009481.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/76bee7464cca/ppat.1009481.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/8046db5f6af6/ppat.1009481.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/2a9a84a81b5d/ppat.1009481.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/5f3c7d69bc66/ppat.1009481.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/f2451e0b1ec9/ppat.1009481.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/fa5cf5f3ca13/ppat.1009481.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/0d1ca08e521e/ppat.1009481.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/d96a3ef06aa6/ppat.1009481.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/76bee7464cca/ppat.1009481.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/8046db5f6af6/ppat.1009481.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/2a9a84a81b5d/ppat.1009481.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/5f3c7d69bc66/ppat.1009481.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/f2451e0b1ec9/ppat.1009481.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ac/8041205/fa5cf5f3ca13/ppat.1009481.g008.jpg

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