The V Protein of Simian Virus 5 Inhibits Interferon Signalling by Targeting STAT1 for Proteasome-Mediated Degradation

Abstract

To replicate in vivo, viruses must circumvent cellular antiviral defense mechanisms, including those induced by the interferons (IFNs). Here we demonstrate that simian virus 5 (SV5) blocks IFN signalling in human cells by inhibiting the formation of the IFN-stimulated gene factor 3 and gamma-activated factor transcription complexes that are involved in activating IFN-α/β- and IFN-γ-responsive genes, respectively. SV5 inhibits the formation of these complexes by specifically targeting STAT1, a component common to both transcription complexes, for proteasome-mediated degradation. Expression of the SV5 structural protein V, in the absence of other virus proteins, also inhibited IFN signalling and induced the degradation of STAT1. Following infection with SV5, STAT1 was degraded in the absence of virus protein synthesis and remained undetectable for up to 4 days postinfection. Furthermore, STAT1 was also degraded in IFN-pretreated cells, even though the cells were in an antiviral state. Since pretreatment of cells with IFN delayed but did not prevent virus replication and protein synthesis, these observations suggest that following infection of IFN-pretreated cells, SV5 remains viable within the cells until they eventually go out of the antiviral state.

Virus growth and antibody responses following respiratory tract infection of ferrets and mice with WT and P/V mutants of the paramyxovirus Simian Virus 5

“…SV5 infection efficiently targets STAT1 for degradation in human cell lines (Didcock et al,1999b;Young et al, 2000), and in tissue culture cells from a number of other species including monkey, dog, and horse, but not rabbit cells (Precious et al, 2005). In our primary cultures of ferret cells, WT SV5 efficiently targeted ferret STAT1 for degradation, whereas the P/V-CPI− mutant which is defective for this property in human cells is also defective in STAT1 degradation in ferret cells.…”

The interferon response circuit: Induction and suppression by pathogenic viruses

“…Third, a given virus may display more than one IFN-antagonistic activity targeting different pathways. Good examples are the V proteins of some paramyxoviruses which bind to the dsRNA-sensing helicase MDA5 and thereby block induction of IFN but also provoke the ubiquitinylation and subsequent degradation of STAT1 in a complex reaction (Didcock et al, 1999;Palosaari et al, 2003;Precious et al, 2005;Ulane et al, 2005). The NSs protein of Rift valley fever virus is a major virulence factor (Bouloy et al, 2001) and blocks IFN production by inhibiting the basic cellular transcription machinery Le May et al, 2004).…”

STAT1 and pathogens, not a friendly relationship

“…The other is the Pneumovirinae subfamily which consists only of the Pneumovirus genus to which the human respiratory syncytial virus (RSV) belongs. The V proteins from the HPIV2, SV5 and MuV target STAT1 for proteasome-mediated degradation [203,204], some proteins target STAT1 only, others target both STAT1 and STAT2, some target only STAT2 and some target STAT3 for degradation. Expression of the V proteins by the simian virus 5 (SV5) and HPIV2 by the human parainfluenza virus type 2 (HPIV2) highjacks the polyubiquitinylation pathways of the cell and induces polyubiquitylation of STAT1 and STAT2 resulting in their degradation by the proteasome, an action that is inhibited by proteasome inhibitors such as lactacystine or MG132 [205].…”