A critical role of interferon-induced protein IFP35 in the type I interferon response in cells induced by foot-and-mouth disease virus (FMDV) protein 2C.

Foot-and-mouth disease virus (FMDV) protein 2C is one of the most highly conserved viral proteins among the serotypes of FMDV. However, its effect on host cell response is not very clear. In our previous report, we showed that FMDV protein 2C interacts with cellular protein N-myc and STAT interactor (Nmi), inducing moderate apoptosis in cells. Here, we show that transfection of HEK293T cells with pEGFP-N1-2C or pEGFP-N1-Nmi induces activation of type I interferon promoters, leading to delayed vesicular stomatitis virus (VSV) growth. Using immunoprecipitation and confocal microscopy assays, we found that interferon-induced protein IFP35 interacts with Nmi. Knockdown of IFP35 expression by siRNA abolished pEGFP-N1-2C and pEGFP-N1-Nmi-induced activation of type I interferon promoters and restored VSV growth, suggesting that IFP35 plays a critical role in the type I interferon response induced by FMDV protein 2C. These findings may help to further understand cell responses to FMDV infection.

Negative Regulation of Hepatic Inflammation by the Soluble Resistance-Related Calcium-Binding Protein via Signal Transducer and Activator of Transcription 3.

Host immune response is tightly controlled by negative regulators to avoid excessive immune reactions for homeostasis. Some pathogens may take advantage of host negative regulating system to evade host defense. Our previous report showed that foot-and-mouth disease virus (FMDV) VP1 inhibited TNF-α- and SeV-induced type I interferon response via interaction with cellular protein soluble resistance-related calcium-binding protein (sorcin). Conversely, TNF-α- or SeV-induced type I interferon response increased when sorcin knocked down, leading to inhibition of vesicular stomatitis virus replication. However, the exact role of sorcin in regulation of the immune response is still not clear. Here, we show that mice deficient of sorcin (sorcin-/-) display enhanced ConA-induced hepatitis. Importantly, splenocytes from sorcin-/- mice produced more IL-2, IL-4, IL-17, and IFN-γ than that of littermate controls (sorcin+/+) in response to anti-CD3/28 stimulation. Furthermore, our data indicate that sorcin interacts with signal transducer and activator of transcription 3 (STAT3) and enhances its phosphorylation and that STAT3 acts as an immediate downstream molecule of sorcin in the negative regulation of NF-κB signaling. Thus, sorcin, in association with STAT3, negatively regulates hepatic inflammation.

Engagement of soluble resistance-related calcium binding protein (sorcin) with foot-and-mouth disease virus (FMDV) VP1 inhibits type I interferon response in cells.

Foot-and-mouth disease (FMD) is an acute, highly contagious animal disease caused by FMD virus (FMDV). Although FMDV-induced immunosuppression in host has been well established, the exact molecular mechanism for such induction is not very clear. We report here the identification of FMDV VP1 as an interferon-suppressor by interacting with soluble resistance-related calcium binding protein (sorcin). We found that VP1 suppressed tumor necrosis factor (TNF)-α or Sendai virus (SeV)-induced type I interferon response in HEK293T cells, and that this suppression could be completely abolished by knockdown of sorcin by shRNA. Furthermore, overexpression of sorcin inhibited type I interferon response. Conversely, TNF- or SeV-induced type I interferon response increased when sorcin knocked down, leading to inhibition of vesicular stomatitis virus (VSV) replication. Thus, VP1-induced suppression of type I interferon is mediated by interacting with sorcin, a protein that appears to regulate cell response to viral infections.