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. 2005 Apr;79(7):4451-9.
doi: 10.1128/JVI.79.7.4451-4459.2005.

Mumps virus V protein antagonizes interferon without the complete degradation of STAT1

Toru Kubota  1 , Noriko Yokosawa, Shin-Ichi Yokota, Nobuhiro Fujii, Masato Tashiro, Atsushi Kato
Affiliations

Mumps virus V protein antagonizes interferon without the complete degradation of STAT1

Toru Kubota et al. J Virol. 2005 Apr.

Abstract

Mumps virus (MuV) has been shown to antagonize the antiviral effects of interferon (IFN) through proteasome-mediated complete degradation of STAT1 by using the viral V protein (T. Kubota et al., Biochem. Biophys. Res. Commun. 283:255-259, 2001). However, we found that MuV could inhibit IFN signaling and the generation of a subsequent antiviral state long before the complete degradation of cellular STAT1 in infected cells. In MuV-infected cells, nuclear translocation and phosphorylation of STAT1 and STAT2 tyrosine residue (Y) at 701 and 689, respectively, by IFN-beta were significantly inhibited but the phosphorylation of Jak1 and Tyk2 was not inhibited. The transiently expressed MuV V protein also inhibited IFN-beta-induced Y701-STAT1 and Y689-STAT2 phosphorylation, suggesting that the V protein could block IFN-beta-induced signal transduction without the aid of other viral components. Finally, a substitution of an alanine residue in place of a cysteine residue in the C-terminal V-unique region known to be required for STAT1 degradation and inhibition of anti-IFN signaling resulted in the loss of V protein function to inhibit the Y701-STAT1 and Y689-STAT2 phosphorylation.

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Figures

FIG. 1.
FIG. 1.
Anti-IFN activity of the MuV RW strain. Cells were preinfected or mock-infected with the RW strain of MuV. The dose of IFN (IU/ml) used for the treatment of cells is indicated at the tops of panels A and B. (A) Cells which survived the VSV challenge infection are stained in black. (B) The MuV P, MuV V, and cellular STAT1 in samples parallel to those in panel A are shown.
FIG. 2.
FIG. 2.
Correlation between STAT degradation and antagonism of the antiviral activity of MuV. The preinfected MuV dose is shown at the top. The IFN doses used for inducing the antiviral state are shown at right. (A) Cells which survived the VSV challenge infection are stained in black. (B) MuV P, MuV V, and cellular STAT1 in samples parallel to those in panel A are shown. The faint band at MuV P at an MOI of 0.006 is nonspecific due to the use of antiserum mixture.
FIG. 3.
FIG. 3.
Inhibition of IFN-β-induced STAT1 nuclear translocation by MuV. MuV-infected CV1 cells were incubated with 0 or 1,000 IU of IFN-β/ml. STAT1 was detected with rabbit polyclonal antibody (left panels), and the MuV HN was detected with mouse monoclonal antibody (middle panels). The merged images are shown in the right panels. Identical microscopic fields of view are shown, and the MuV HN and STAT1 are shown in red and green, respectively.
FIG. 4.
FIG. 4.
The effect of MuV infection on IFN-β-induced phosphorylation of signaling molecules. Cells infected with MuV at an MOI of 5.0 and uninfected cells were treated with 0 or 1,000 IU of IFN-β/ml at 48 h postinfection. The MuV P, MuV V, STAT1, and pY701-STAT1 are shown (A); STAT2 and pY609-STAT2 (B), Jak1 and pY-Jak1 (C), and Tyk2 and pY-Tyk2 (D) are also shown.
FIG. 5.
FIG. 5.
Inhibition of IFN-β-induced Y701-STAT1 phosphorylation by MuV V protein. The MuV V of the Torii strain expressing plasmid DNA (pTM-V) transiently transfected to Vero cells is shown at the top (A). The MuV V, STAT1, and pY701-STAT1 detected in the cells treated with 1,000 IU of IFN-β/ml for 0 or 30 min are shown. Vero cells (B) or CV1 cells (C) transiently transfected with 0 μg (none) or 1 μg (V transfection) of pTM-V were subsequently treated with 1,000 IU of IFN-β/ml for the indicated times. STAT1 and pY701-STAT1 detected in the cells are shown.
FIG. 6.
FIG. 6.
Involvement of C-terminal cysteine residues of the MuV V protein for the inhibition of IFN-β-induced STAT1 phosphorylation. The plasmid DNAs able to express parental V protein of the Torii strain (Vwt) or three mutant V proteins (Vc189a, Vc207a, and Vc214a) were transiently transfected to CV1 cells. The cells were incubated with 1,000 IU of IFN-β/ml for the indicated times shown above the gels. STAT1, pY701-STAT1, STAT2, pY689-STAT2, and MuV V detected in the cells are shown.
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