TcpC inhibits neutrophil extracellular trap formation by enhancing ubiquitination mediated degradation of peptidylarginine deiminase 4

Qian Ou, Jia-qi Fang, Zhe-sheng Zhang, Zhe Chi, Jie Fang, Di-yan Xu, Kai-zhong Lu, Meng-qing Qian, Da-yong Zhang, Jun-ping Guo, Wei Gao, Na-ru Zhang and Jian-ping Pan ()
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Qian Ou: Zhejiang University City College
Jia-qi Fang: Zhejiang University City College
Zhe-sheng Zhang: Zhejiang University City College
Zhe Chi: Zhejiang University City College
Jie Fang: Zhejiang University City College
Di-yan Xu: Zhejiang University City College
Kai-zhong Lu: Zhejiang University City College
Meng-qing Qian: Zhejiang University City College
Da-yong Zhang: Zhejiang University City College
Jun-ping Guo: Zhejiang University City College
Wei Gao: Zhejiang University City College
Na-ru Zhang: Zhejiang University City College
Jian-ping Pan: Zhejiang University City College

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract TcpC is a multifunctional virulence factor of uropathogenic E. coli (UPEC). Neutrophil extracellular trap formation (NETosis) is a crucial anti-infection mechanism of neutrophils. Here we show the influence of TcpC on NETosis and related mechanisms. We show NETosis in the context of a pyelonephritis mouse model induced by TcpC-secreting wild-type E. coli CFT073 (CFT073wt) and LPS-induced in vitro NETosis with CFT073wt or recombinant TcpC (rTcpC)-treated neutrophils are inhibited. rTcpC enters neutrophils through caveolin-mediated endocytosis and inhibits LPS-induced production of ROS, proinflammatory cytokines and protein but not mRNA levels of peptidylarginine deiminase 4 (PAD4). rTcpC treatment enhances PAD4 ubiquitination and accumulation in proteasomes. Moreover, in vitro ubiquitination kit analyses show that TcpC is a PAD4-targetd E3 ubiquitin-ligase. These data suggest that TcpC inhibits NETosis primarily by serving as an E3 ligase that promotes degradation of PAD4. Our findings provide a novel mechanism underlying TcpC-mediated innate immune evasion.

Date: 2021
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DOI: 10.1038/s41467-021-23881-8

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