Abstract
Foot-and-mouth disease virus (FMDV) is the etiological agent of FMD, which affects cloven-hoofed animals. The pathophysiology of FMDV has not been fully understood and the evasion of host innate immune system is still unclear. Here, the FMDV non-structural protein 3A was identified as a negative regulator of virus-triggered IFN-β signaling pathway. Overexpression of the FMDV 3A inhibited Sendai virus-triggered activation of IRF3 and the expressions of RIG-I/MDA5. Transient transfection and co-immunoprecipitation experiments suggested that FMDV 3A interacts with RIG-I, MDA5 and VISA, which is dependent on the N-terminal 51 amino acids of 3A. Furthermore, 3A also inhibited the expressions of RIG-I, MDA5, and VISA by disrupting their mRNA levels. These results demonstrated that 3A inhibits the RLR-mediated IFN-β induction and uncovered a novel mechanism by which the FMDV 3A protein evades the host innate immune system.
Highlights
IFN regulatory factor 3 (IRF3)/719, cleaving ubiquitin moieties from critical signaling proteins of the type I IFN signaling pathway, and/or abrogating the deubiquitinating activity of enzymes[20]
In real-time PCR experiments, it was observed that Sendai virus (SeV)-triggered transcriptions of the Ifnb[1], Cxcl-10, Isg[56] and Rantes genes were decreased in Foot-and-mouth disease virus (FMDV) 3A-transfected cells in comparison with the control transfected cells (Fig. 1g)
It was found that overexpression of the FMDV 3A inhibited IRF3 phosphorylation and dimerization, which are hallmarks for IRF3 activation (Fig. 1j), in addition, overexpression of FMDV 3A decreased the expressions of retinoic acid-inducible gene-I (RIG-I)/MDA5 after SeV infection (Fig. 1k)
Summary
IRF3/719, cleaving ubiquitin moieties from critical signaling proteins of the type I IFN signaling pathway, and/or abrogating the deubiquitinating activity of enzymes[20]. FMDV VP1 suppresses type I IFN induction by interacting with sorcin, which appears to regulate the cellular response to viral infections[22]. It remains unclear whether other FMDV nonstructural proteins are involved in inhibition of type I IFN signaling. The results demonstrated that FMDV 3A inhibited virus-triggered the IFN-β signaling pathway. It inhibited the expression of RIG-I, MDA5 and VISA proteins by disrupting their mRNA levels. It uncovered the complicated mechanisms underlying the evasion of the host immune response by FMDV
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