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Foot-and-Mouth Disease Virus 3B Protein Interacts with Pattern Recognition Receptor RIG-I to Block RIG-I-Mediated Immune Signaling and Inhibit Host Antiviral Response.

ABSTRACT: Foot-and-mouth disease is a highly contagious disease of pigs, sheep, goats, bovine, and various wild cloven-hoofed animals caused by foot-and-mouth disease virus (FMDV) that has given rise to significant economic loss to global livestock industry. FMDV 3B protein is an important determinant of virulence of the virus. Modifications in 3B protein of FMDV considerably decrease virus yield. In the current study, we demonstrated the significant role of 3B protein in suppression of type I IFN production and host antiviral response in both human embryonic kidney HEK293T cells and porcine kidney PK-15 cells. We found that 3B protein interacted with the viral RNA sensor RIG-I to block RIG-I-mediated immune signaling. 3B protein did not affect the expression of RIG-I but interacted with RIG-I to block the interaction between RIG-I and the E3 ubiquitin ligase TRIM25, which prevented the TRIM25-mediated, Lys63-linked ubiquitination and activation of RIG-I. This inhibition of RIG-I-mediated immune signaling by 3B protein decreased IFN-?, IFN-stimulated genes, and proinflammatory cytokines expression, which in turn promoted FMDV replication. All of the three nonidentical copies of 3B could inhibit type I IFN production, and the aa 17A in each copy of 3B was involved in suppression of IFN-related antiviral response during FMDV infection in porcine cells. Together, our results indicate the role of 3B in suppression of host innate immune response and reveal a novel antagonistic mechanism of FMDV that is mediated by 3B protein.

SUBMITTER: Zhang X

PROVIDER: S-EPMC7533709 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Foot-and-Mouth Disease Virus 3B Protein Interacts with Pattern Recognition Receptor RIG-I to Block RIG-I-Mediated Immune Signaling and Inhibit Host Antiviral Response.

Zhang Xiangle X Zhu Zixiang Z Wang Congcong C Yang Fan F Cao Weijun W Li Pengfei P Du Xiaoli X Zhao Furong F Liu Xiangtao X Zheng Haixue H

Journal of immunology (Baltimore, Md. : 1950) 20200911 8

Foot-and-mouth disease is a highly contagious disease of pigs, sheep, goats, bovine, and various wild cloven-hoofed animals caused by foot-and-mouth disease virus (FMDV) that has given rise to significant economic loss to global livestock industry. FMDV 3B protein is an important determinant of virulence of the virus. Modifications in 3B protein of FMDV considerably decrease virus yield. In the current study, we demonstrated the significant role of 3B protein in suppression of type I IFN product ...[more]

PMID: 32917788

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Project description:The role of retinoic acid-inducible gene I (RIG-I) in foot-and-mouth disease virus (FMDV)-infected cells remains unknown. Here, we showed that RIG-I inhibits FMDV replication in host cells. FMDV infection increased the transcription of RIG-I, while it decreased RIG-I protein expression. A detailed analysis revealed that FMDV leader proteinase (Lpro), as well as 3C proteinase (3Cpro) and 2B protein, decreased RIG-I protein expression. Lpro and 3Cpro are viral proteinases that can cleave various host proteins and are responsible for several of the viral polyprotein cleavages. However, for the first time, we observed 2B-induced reduction of host protein. Further studies showed that 2B-mediated reduction of RIG-I is specific to FMDV, but not other picornaviruses, including encephalomyocarditis virus, enterovirus 71, and coxsackievirus A16. Moreover, we found the decreased protein level of RIG-I is independent of the cleavage of eukaryotic translation initiation factor 4 gamma, the induction of cellular apoptosis, or the association of proteasome, lysosome, and caspase pathways. A direct interaction was observed between RIG-I and 2B. The carboxyl-terminal amino acids 105 to 114 and amino acids 135 to 144 of 2B were essential for the reduction of RIG-I, while residues 105 to 114 were required for the interaction. These data suggest the antiviral role of RIG-I against FMDV and a novel antagonistic mechanism of FMDV that is mediated by 2B protein.ImportanceThis study demonstrated that RIG-I could suppress FMDV replication during virus infection. FMDV infection increased the transcriptional expression of RIG-I, while it decreased RIG-I protein expression. FMDV 2B protein interacted with RIG-I and induced reduction of RIG-I. 2B-induced reduction of RIG-I was independent of the induction of the cleavage of eukaryotic translation initiation factor 4 gamma or cellular apoptosis. In addition, proteasome, lysosome, and caspase pathways were not involved in this process. This study provides new insight into the immune evasion mediated by FMDV and identifies 2B as an antagonistic factor for FMDV to evade the antiviral response.

Dataset Information

Foot-and-Mouth Disease Virus 3B Protein Interacts with Pattern Recognition Receptor RIG-I to Block RIG-I-Mediated Immune Signaling and Inhibit Host Antiviral Response.

Publications

Foot-and-Mouth Disease Virus 3B Protein Interacts with Pattern Recognition Receptor RIG-I to Block RIG-I-Mediated Immune Signaling and Inhibit Host Antiviral Response.

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