Subversion of GBP-mediated host defense by E3 ligases acquired during Yersinia pestis evolution

Shiyang Cao, Yang Jiao, Wei Jiang, Yarong Wu, Si Qin, Yifan Ren, Yang You, Yafang Tan, Xiao Guo, Hongyan Chen, Yuan Zhang, Gengshan Wu, Tong Wang, Yazhou Zhou, Yajun Song, Yujun Cui, Feng Shao, Ruifu Yang () and Zongmin Du ()
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Shiyang Cao: Beijing Institute of Microbiology and Epidemiology
Yang Jiao: Beijing Institute of Microbiology and Epidemiology
Wei Jiang: National Institute of Biological Sciences
Yarong Wu: Beijing Institute of Microbiology and Epidemiology
Si Qin: Beijing Institute of Microbiology and Epidemiology
Yifan Ren: Beijing Institute of Microbiology and Epidemiology
Yang You: Beijing Institute of Microbiology and Epidemiology
Yafang Tan: Beijing Institute of Microbiology and Epidemiology
Xiao Guo: Beijing Institute of Microbiology and Epidemiology
Hongyan Chen: Beijing Institute of Microbiology and Epidemiology
Yuan Zhang: Beijing Institute of Microbiology and Epidemiology
Gengshan Wu: Beijing Institute of Microbiology and Epidemiology
Tong Wang: Beijing Institute of Microbiology and Epidemiology
Yazhou Zhou: Beijing Institute of Microbiology and Epidemiology
Yajun Song: Beijing Institute of Microbiology and Epidemiology
Yujun Cui: Beijing Institute of Microbiology and Epidemiology
Feng Shao: National Institute of Biological Sciences
Ruifu Yang: Beijing Institute of Microbiology and Epidemiology
Zongmin Du: Beijing Institute of Microbiology and Epidemiology

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Plague has caused three worldwide pandemics in history, including the Black Death in medieval ages. Yersinia pestis, the etiological agent of plague, has evolved a powerful arsenal to disrupt host immune defenses during evolution from enteropathogenic Y. pseudotuberculosis. Here, we find that two functionally redundant E3 ligase of Y. pestis, YspE1 and YspE2, can be delivered via type III secretion injectisome into host cytosol where they ubiquitinate multiple guanylate-binding proteins (GBPs) for proteasomal degradation. However, Y. pseudotuberculosis has no such capability due to lacking functional YspE1/2 homologs. YspE1/2-mediated GBP degradations significantly promote the survival of Y. pestis in macrophages and strongly inhibit inflammasome activation. By contrast, Gbpchr3−/−, chr5−/− macrophages exhibit much lowered inflammasome activation independent of YspE1/2, accompanied with an enhanced replication of Y. pestis. Accordingly, Gbpchr3−/−, chr5−/− mice are more susceptible to Y. pestis. We demonstrate that Y. pestis utilizes E3 ligases to subvert GBP-mediated host defense, which appears to be newly acquired by Y. pestis during evolution.

Date: 2022
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DOI: 10.1038/s41467-022-32218-y

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