Foot-and-Mouth Disease Virus Viroporin 2B Antagonizes RIG-I-Mediated Antiviral Effects by Inhibition of Its Protein Expression

Abstract

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.IMPORTANCE This 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.

Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage

“…Previous studies have reported that picornaviruses exert various strategies to evade host innate immune responses through certain viral proteins, such as L pro , VP2, VP3, 2A pro , 2C pro , 3A pro , and 3C pro (17,18,(25)(26)(27)(28)(29)(30)(31). In this study, we found that the overexpression of SVV proteins VP2, 3C pro , and 3D reduced Sev-induced IFN-␤ production (Fig.…”

“…As a result, IFN production and signal transduction are suppressed. FMDV infection restricts the expression of RIG-I, DMA5, and MAVS to attenuate host innate immune responses (18,27,29). FMDV can also target NEMO to cleave it to inhibit NF-B-and IRF3-mediated IFN production (30).…”

“…Previous studies have reported that picornaviruses utilize different strategies to inhibit host proteins translation, particularly through L pro -and 3C pro -mediated the cleavage of eIF4G (43)(44)(45)(46). A recent study identified FMDV 2B protein as a novel antagonism factor to counteract RIG-I-mediated antiviral response by reducing protein abundance of RIG-I (27). Less is known about SVV and host cellular translation.…”

Foot-and-mouth disease virus induces lysosomal degradation of host protein kinase PKR by 3C proteinase to facilitate virus replication

“…Detection of house keeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was also conducted for normalization of total input RNA. Relative transcript levels were calculated by 2 −ΔΔCT (where CT is threshold cycle) method as previously described (Zhu et al, 2016). The primers used in this study were shown in Table 1.…”

Molecular Mechanisms of Foot-and-Mouth Disease Virus Targeting the Host Antiviral Response

“…Zhu et al observed that RIG-I protein was gradually downregulated as infection progresses (Zhu et al, 2016). Expression of RIG-I inhibited FMDV replication in a dose-dependent manner whereas an enhancement was observed in RIG-I siRNA PK-15 cells.…”