Dual Functions of Rift Valley Fever Virus NSs Protein: Inhibition of Host mRNA Transcription and Post‐transcriptional Downregulation of Protein Kinase PKR

Abstract

Rift Valley fever virus (RVFV), which belongs to the genus Phlebovirus, family Bunyaviridae, is a negative-stranded RNA virus carrying a single-stranded, tripartite RNA genome. RVFV is an important zoonotic pathogen transmitted by mosquitoes and causes large outbreaks among ruminants and humans in Africa and the Arabian Peninsula. Human patients develop an acute febrile illness, followed by a fatal hemorrhagic fever, encephalitis or ocular diseases. A viral nonstructural protein, NSs, is a major viral virulence factor. Past studies showed that NSs suppresses the transcription of host mRNAs, including interferon-β mRNAs. Here we demonstrated that the NSs protein induced post-transcriptional downregulation of dsRNA-dependent protein kinase, PKR, to prevent phosphorylation of eIF2α and promoted viral translation in infected cells. These two biological activities of the NSs most probably have a synergistic effect in suppressing host innate immune functions and facilitate efficient viral replication in infected mammalian hosts.

Curcumin Inhibits Rift Valley Fever Virus Replication in Human Cells

“…The S (small) segment encodes the N protein and a second nonstructural protein, NSs. NSs, a viral virulence factor, is a transcriptional repressor critical to the down-regulation of the host interferon response (7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

Single-Dose Immunization with Virus Replicon Particles Confers Rapid Robust Protection against Rift Valley Fever Virus Challenge

“…Deletions of NSm (6) and NSs (38) have been shown to reduce virulence of RVFV in adult rodents. The NSs protein inhibits the host immune response to RVFV infection through multiple mechanisms (3,16,18,25,26); therefore, its absence or mutation is a common feature of many RVF vaccine candidates (5,13). Additional full-length deletions of genes encoding the structural proteins Gn and Gc confine VRP RVF replication to the initially infected cells.…”

“…The ambisense small (S) segment encodes, in the viral sense, the nucleoprotein (NP) that is required for RNA synthesis, and the nonstructural NSs protein in the opposite orientation. NSs is the major RVFV virulence factor and functions to inhibit the host immune response (9) by generalized downregulation of host transcription (3,25), posttranscriptional degradation of protein kinase R (PKR) (16,18), and repression of the beta interferon (IFN-␤) promoter (26). Previous work has indicated the importance of both NSm (6) and NSs (1,38) in determining virulence in vivo.…”

Dicer-2- and Piwi-Mediated RNA Interference in Rift Valley Fever Virus-Infected Mosquito Cells

“…This viral protein forms filaments in nuclei of infected mammalian cells (38)(39)(40) and inhibits basal cellular transcription and interferon-␤ gene transcription via the interaction of NSs with, respectively, the p44 and p62 subunits of the TFIIH general transcription factor (41,42) and the SAP30 subunit of the Sin3A repressor complex (43). NSs was also shown to downregulate the expression of PKR by degrading the protein through the proteasome pathway (44)(45)(46). In addition, NSs interacts with gamma satellite pericentromeric sequences, provoking abnormal nuclei during cell division (38).…”