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- Title
Subversion of GBP-mediated host defense by E3 ligases acquired during Yersinia pestis evolution.
- Authors
Cao, Shiyang; Jiao, Yang; Jiang, Wei; Wu, Yarong; Qin, Si; Ren, Yifan; You, Yang; Tan, Yafang; Guo, Xiao; Chen, Hongyan; Zhang, Yuan; Wu, Gengshan; Wang, Tong; Zhou, Yazhou; Song, Yajun; Cui, Yujun; Shao, Feng; Yang, Ruifu; Du, Zongmin
- 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. Guanylate-binding proteins (GBPs) recognize pathogen containing vacuoles, leading to lysis of this intracellular niche and induction of inflammasomes. Here, Cao et al. show that Y. pestis, the causative agent of plague, secret two functionally redundant E3 ligase, YspE1 and YspE2, into the host's cytosol to ubiquitinate multiple GBPs for proteasomal degradation to subvert host immune defense. This capability appears to be newly acquired by Y. pestis during evolution, since its closely related progenitor Y. pseudotuberculosis is unable to do so.
- Subjects
YERSINIA pestis; LIGASES; YERSINIA pseudotuberculosis; BLACK Death pandemic, 1348-1351; INFLAMMASOMES
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-32218-y