Seneca Valley Virus 3Cpro abrogates the IRF3- and IRF7-mediated innate immune response by degrading IRF3 and IRF7

Abstract

Seneca Valley Virus (SVV) is a newly emerged virus belonging to the family Picornaviridae. Basic knowledge of the immunological response to SVV is limited. To date, one study has demonstrated that SVV 3C mediates the cleavage of host MAVS, TRIF, and TANK at specific sites and consequently escapes the host's antiviral innate immunity. In this study, we show that SVV 3C reduces IRF3 and IRF7 protein expression level and phosphorylation. SVV infection also reduces expression of IRF3 and IRF7 protein. The degradation of IRF3 and IRF7 is dependent on the 3C protease activity. We also identify interactions between 3C and IRF3 and IRF7 in PK-15 cells. A detailed analysis revealed that the degradation of IRF3 and IRF7 blocks the transcription of IFN-β, IFN-α1, IFN-α4, and ISG54. Together, our results demonstrate a novel mechanism developed by SVV 3C to allow the virus to escape the host's intrinsic innate immune system.

Seneca Valley Virus 3C protease negatively regulates the type I interferon pathway by acting as a viral deubiquitinase

“…Sequences (5′-3′) Target gene Xue et al Antiviral Research 160 (2018) 183-189 endogenous transcription of the IFN-β and ISG54 genes. Studies have indicated that SVV 3C pro mutants that abrogate Cys and His residues lost protease activity (Qian et al, 2017;Xue et al, 2018). Here, our results indicated that SVV 3C pro mutants that abrogate Cys and His residues also lost DUB activity.…”

“…SVV was first isolated in the United States in 2002 as a contaminant in the cell culture of human fetal retinoblasts (Segales et al, 2017). Afterward, a large number of SVV infections, which were characterized by porcine idiopathic vesicular disease, were observed in the United States, Canada, Brazil, and China (Xue et al, 2018). In China, the first case of SVV infection was identified in Guangdong Province in 2015 .…”

“…For instance, human immunodeficiency virus-1 inhibits the antiviral response by the ub-mediated degradation of IRF3 (Okumura et al, 2008), porcine reproductive and respiratory syndrome (PRRS) virus inhibits nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) activation by inhibition of the polyubiquitination process of IĸBα . To date, SVV 3C pro has evolved mechanism to cleave or degrade innate immune adaptors to escape the host antiviral innate immune response (Qian et al, 2017;Xue et al, 2018). However, other mechanisms that enable SVV to escape the host innate immune response remain unclear.…”

“…SVV 3C pro contains Cys and His residues. Therefore, the three mutants, namely the single-site mutants H48A or C160A, and the doublesites mutants H48A/C160A (3Cdm) (Xue et al, 2018), were used to confirm whether the Cys and His residues are involved in the DUB activity of SVV 3C pro . HEK293T cells were co-transfected with HA-Ub-, HA-K63-Ub-, and FLAG-K48-Ub-expressing plasmids along with FLAG-3C-expressing plasmid or FLAG-3C mutants expressing plasmids.…”

Grass carp reovirus VP56 represses interferon production by degrading phosphorylated IRF7

“…For instance, porcine reproductive and respiratory syndrome (PRRS) utilizes the nsp 7 protein to inhibit IRF7 expression, thereby down-regulating IFN production and counteracting the host antiviral state [30]. The 3C pro of Seneca Valley Virus (SVV) reduces IRF3 and IRF7 protein expression and phosphorylation via its protease activity, thus blocking IFN transcription to escape the host immune response [31]. Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded viral interferon regulatory factor 4 (vIRF4) interacts with IRF7, resulting in the inhibition of IRF7 dimerization and ultimately suppressing IFN production [32].…”