The V Protein of Human Parainfluenza Virus 2 Antagonizes Type I Interferon Responses by Destabilizing Signal Transducer and Activator of Transcription 2

Abstract

Type I interferon (IFN) induces antiviral responses through the activation of the ISGF3 transcription factor complex that contains the subunit proteins STAT1, STAT2, and p48/ISGF3 gamma/IRF9. The ability of some human paramyxoviruses to overcome IFN actions by specific proteolysis of STAT proteins has been examined. Infection of cells with type 2, but not type 1 or type 3 human parainfluenza virus (HPIV) leads to a loss of cellular STAT2 protein. Expression of a single HPIV2 protein derived from the V open reading frame blocks IFN-dependent transcriptional responses in the absence of other viral proteins. The loss of IFN response is due to V-protein-induced proteolytic degradation of STAT2. Expression of HPIV2 V causes the normally stable STAT2 protein to be rapidly degraded, and this proteolytic activity can be partially alleviated by proteasome inhibition. No V-protein-specific effects on STAT2 mRNA levels were observed. The results indicate that the V protein of HPIV2 is sufficient to recognize and target a specific cellular transcription factor for destruction by cellular machinery.

Identification of the Nuclear Export Signal and STAT-Binding Domains of the Nipah Virus V Protein Reveals Mechanisms Underlying Interferon Evasion

“…Current evidence from the study of several family members indicates that the common outcome of STAT targeting and IFN evasion is achieved by individual paramyxovirus species through a diverse range of molecular mechanisms. For example, the Rubulaviruses, simian virus 5 (SV5), human parainfluenza virus 2, and mumps virus all encode STAT-directed E3 ubiquitin ligase activities that function in combination with cellular proteins to target STAT1, STAT2, or STAT3 for proteasomal degradation (5,18,19,28,29). Distinctly, measles virus, a prototype Morbillivirus, does not induce STAT ubiquitylation and degradation but instead prevents IFN-induced ISGF3 assembly and STAT protein nuclear translocation (17, 27).…”

The STAT2 Activation Process Is a Crucial Target of Sendai Virus C Protein for the Blockade of Alpha Interferon Signaling

“…The V protein of rubulavirus simian virus 5 targets a key factor, signal transducer and activator of transcription 1 (STAT1), on interferon (IFN) signaling for proteasome-mediated degradation, thereby inhibiting IFN signal transduction (1,3,6,7,33,35,48,49). The V proteins of other rubulaviruses, including human parainfluenza virus type 2, mumps virus, and simian virus 41 inhibit IFN signaling likewise by inducing a decrease in the STAT1 or STAT2 level (8,25,30,31,34,35,47,49). In contrast, the respirovirus Sendai virus (SeV), which possesses both V and C ORFs, has evolved functions of the C protein instead of the V protein so as to block IFN signaling (12,18).…”

Suppression of Thermotolerance in Mumps Virus-infected Cells Is Caused by Lack of HSP27 Induction Contributed by STAT-1

“…Mumps virus and simian virus 5 accelerate the degradation of STAT-1 protein in a proteasome-dependent manner (19 -21). Human parainfluenza virus type 2 reduces STAT-2 protein levels (22,23). Accelerated degradation of STAT-1 by mumps virus is necessary and sufficient for the expression of viral accessory protein V (20,21,24).…”