1. A phosphodiesterase CpdB in Yersinia pseudotuberculosis degrades CDNs to inhibit innate immune response.
- Author
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Wang X, Hao X, Yang Y, Jia S, Chen Y, Yang W, Luo Y, Xie Z, Gu Y, Wu Y, Zhang F, Li M, Wang Y, Shen X, and Xu L
- Subjects
- Animals, Mice, Bacterial Proteins genetics, Bacterial Proteins metabolism, Nucleotides, Cyclic metabolism, Macrophages immunology, Macrophages microbiology, Dinucleoside Phosphates metabolism, Female, Cyclic GMP analogs & derivatives, Yersinia pseudotuberculosis immunology, Yersinia pseudotuberculosis genetics, Immunity, Innate, Phosphoric Diester Hydrolases genetics, Phosphoric Diester Hydrolases metabolism, Yersinia pseudotuberculosis Infections immunology, Yersinia pseudotuberculosis Infections microbiology
- Abstract
Yersinia pseudotuberculosis (Yptb) is a pathogenic gram-negative bacterium that can colonize the intestines of different animals. Its infection leads to the activation of the host's innate immunity. Both host and bacterial-derived cyclic dinucleotides (CDNs) could activate the innate immune response of host cells. In bacteria, CDNs like c-di-AMP, c-di-GMP, or 3'3'-cGAMP can be hydrolyzed by different hydrolases. Recent studies showed that the degradation of those second messengers helps the pathogen evade immune detection. In this study, we identified a hydrolase, YPK_3776, namely CpdB in Yptb. CpdB is predicted to bind bacterial-derived c-di-AMP, c-di-GMP, 3'3'-cGAMP and host-derived 2'3'-cGAMP. Surprisingly, by using high-performance liquid chromatography (HPLC), we found that CpdB could only degrade bacterial-derived CDNs but not host-derived 2'3'-cGAMP. In addition, CpdB has 2'3'-cNMP activity. Consistently, the Yptb mutant lacking the cpdB gene exhibited a higher level of intracellular c-di-GMP. Furthermore, the ∆cpdB mutant elicited stronger innate immune responses during Yptb infection in macrophages, suggesting CpdB enables Yptb to evade host immune surveillance. Furthermore, CpdB inhibited the Yptb-induced innate immune response in a STING-dependent manner. Finally, we showed the ∆cpdB infection in mice model exhibited in lower bacterial burden, as compared to wild-type strain infection, indicating CpdB is important for bacterial survival in the host. Together, we identified a cyclic dinucleotide hydrolase CpdB in Yptb that could degrade bacterial-derived CDNs which help the pathogen to evade immune detection via the STING pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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