3C ^pro of Foot-and-Mouth Disease Virus Antagonizes the Interferon Signaling Pathway by Blocking STAT1/STAT2 Nuclear Translocation

Abstract

Foot-and-mouth disease virus (FMDV) causes a highly contagious, debilitating disease in cloven-Further mechanistic studies demonstrated that 3C pro induced proteasome-and caspase-independent protein degradation of karyopherin ␣1 (KPNA1), the nuclear localization signal receptor for tyrosine-phosphorylated STAT1, but not karyopherin ␣2, ␣3, or ␣4. Finally, we showed that the protease activity of 3C pro contributed to the degradation of KPNA1 and thus blocked STAT1/STAT2 nuclear translocation. Taken together, results of our experiments describe for the first time a novel mechanism by which FMDV evolves to inhibit IFN signaling and counteract host innate antiviral responses. IMPORTANCE We show that 3Cpro of FMDV antagonizes the JAK-STAT signaling pathway by blocking STAT1/STAT2 nuclear translocation. Furthermore, 3C pro induces KPNA1 degradation, which is independent of proteasome and caspase pathways. The protease activity of 3C pro contributes to the degradation of KPNA1 and governs the ability of 3C pro to inhibit the JAK-STAT signaling pathway. This study uncovers a novel mechanism evolved by FMDV to antagonize host innate immune responses.

Foot-and-mouth disease virus structural protein VP3 degrades Janus kinase 1 to inhibit IFN-γ signal transduction pathways

“…21 We showed that FMDV VP3 does not induce the downregulation of STAT1, but it prevents IFN-g-induced STAT1-activated tyrosine phosphorylation and blocks the nuclear accumulation of phosphorylated STAT1.…”

“…It was recently reported that 3C pro antagonizes the type I IFN signaling pathway by blocking STAT1/STAT2 nuclear translocation. 21 FMDV VP1-induced suppression of type I IFNs is mediated by interactions with sorcin that appear to regulate the cellular response to viral infections. 22 However, whether other FMDV proteins are involved in inhibiting type II IFN signaling remains unclear, and the associated mechanisms are unknown.…”

Diversification of importin-α isoforms in cellular trafficking and disease states

“…PRRSV protein Nsp1β mediates this degradation by causing an increase in ubiquitination of importin α5, although the mechanism for this is unknown [130]. Similar behaviour is seen from the foot-and-mouth-disease virus protein 3C pro (see Table 2), which has protease activity and directly degrades importin α5 [131]. There are also endogenous approaches to targeted degradation of importin α, implemented as a response to viral infection or during cell death.…”

Picornavirus IRES elements: RNA structure and host protein interactions

“…Next, eIF5B together with eIF1A promotes the recruitment of the 60S subunit. Finally, ribosomal subunit joining promotes GTP hydrolysis by eIF5B, which dissociates together with eIF1A, leaving a competent (Du et al, 2014) 80S ribosome with a Met-tRNA i in the P-site ready for translation elongation (reviewed in Parsyan et al, 2011).…”