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

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 p...

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Main Authors: Fang, Jia-qi (Author) , Ou, Qian (Author) , Pan, Jun (Author) , Fang, Jie (Author) , Zhang, Da-yong (Author) , Qiu, Miao-qi (Author) , Li, Yue-qi (Author) , Wang, Xiao-Hui (Author) , Yang, Xue-yu (Author) , Chi, Zhe (Author) , Gao, Wei (Author) , Guo, Jun-ping (Author) , Miethke, Thomas (Author) , Pan, Jian-ping (Author)
Format: Article (Journal)
Language:English
Published: March 31, 2021
In: PLoS pathogens
Year: 2021, Volume: 17, Issue: 3, Pages: 1-22
ISSN:1553-7374
DOI:10.1371/journal.ppat.1009481
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1371/journal.ppat.1009481
Verlag, lizenzpflichtig, Volltext: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009481
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Author Notes:Jia-qi Fang, Qian Ou, Jun Pan, Jie Fang, Da-yong Zhang, Miao-qi Qiu, Yue-qi Li, Xiao-Hui Wang, Xue-yu Yang, Zhe Chi, Wei Gao, Jun-ping Guo, Thomas Miethke, Jian-ping Pan
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Summary: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.
Item Description:Gesehen am 08.09.2021
Physical Description:Online Resource
ISSN:1553-7374
DOI:10.1371/journal.ppat.1009481

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