Rotavirus NSP1 Inhibits Expression of Type I Interferon by Antagonizing the Function of Interferon Regulatory Factors IRF3, IRF5, and IRF7

Abstract

Secretion of interferon (IFN) by virus-infected cells is essential for activating autocrine and paracrinepathways that promote cellular transition to an antiviral state. In most mammalian cells, IFN production is initiated by the activation of constitutively expressed IFN regulatory factor 3, IRF3, which in turn leads to the induction of IRF7, the "master regulator" of IFN type I synthesis (alpha/beta IFN). Previous studies established that rotavirus NSP1 antagonizes IFN signaling by inducing IRF3 degradation. In the present study, we have determined that, in comparison to wild-type rotaviruses, rotaviruses encoding defective NSP1 grow to lower titers in some cell lines and that this poor growth phenotype is due to their failure to suppress IFN expression. Furthermore, we provide evidence that rotaviruses encoding wild-type NSP1 subvert IFN signaling by inducing the degradation of not only IRF3, but also IRF7, with both events occurring through proteasomedependent processes that proceed with similar efficiencies. The capacity of NSP1 to induce IRF7 degradation may allow rotavirus to move across the gut barrier by enabling the virus to replicate in specialized trafficking cells (dendritic cells and macrophages) that constitutively express IRF7. Along with IRF3 and IRF7, NSP1 was found to induce the degradation of IRF5, a factor that upregulates IFN expression and that is involved in triggering apoptosis during viral infection. Our analysis suggests that NSP1 mediates the degradation of IRF3, IRF5, and IRF7 by recognizing a common element of IRF proteins, thereby allowing NSP1 to act as a broad-spectrum antagonist of IRF function.

A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection

“…Rotavirus antagonizes IFN production pretranscriptionally in a variety of cell lines (HT29, Caco-2, and 293T) through degradation of factors involved in IFN transcription (35,(49)(50)(51). We observed robust type III IFN transcription with HRV and poly (I:C) treatment (∼100-1,000-fold increases; Fig.…”

Human Immunodeficiency Virus Type 1 Mediates Global Disruption of Innate Antiviral Signaling and Immune Defenses within Infected Cells

“…HIV-1 is not unique in targeting IRF-3 as a countermeasure to host innate defenses, as other viruses have been shown to antagonize IRF-3 function through disruption of upstream signaling programs (27) and degradation of IRF-3 during infection (3,4,15). While HIV-1 targeting of IRF-3 is particularly effective in disrupting several host PRR pathways, we found that IRF-9-dependent IFN signaling and PRR signaling of NF-B remain intact in HIV-1-infected cells.…”

The Early Interferon Response to Rotavirus Is Regulated by PKR and Depends on MAVS/IPS-1, RIG-I, MDA-5, and IRF3

“…The rotavirus gene segment encoding the nonstructural protein 1 (NSP1) is an important determinant of host restriction of viral replication both in vitro (17,53) and in vivo (9). Specifically, we along with others have reported a role for NSP1 in regulating the ability of rotavirus to efficiently cause diarrhea in mice (9), spread from animal to animal (9), replicate in vivo and in vitro (4,(15)(16)(17), and antagonize IFN (4,5,17,24,25,53). Thus, the host innate immune response is an important determinant of rotavirus host range restriction and depends on both the virus strain and host cell or tissue type.…”

“…At least two distinct mechanisms by which rotaviruses inhibit the host IFN response have been reported: (i) NSP1-mediated proteasomal degradation of host transcription factors IRF3 and IRF7, resulting in diminished IFN-␤ gene transcription and antiviral activity (4,5), and (ii) proteasomal degradation of ␤-TrCP, leading to inhibition of NF-B activity and subsequent IFN-␤ gene transcription (24). In contrast to these examples, we reported that the UK bovine rotavirus strain was unable to block IFN-␤ secretion in murine fibroblasts (17), and this correlated with the lack of murine IRF3 degradation by UK NSP1 (53).…”