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Journal of Virology, March 2003, p. 3360-3370, Vol. 77, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.6.3360-3370.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Bin Gotoh,1* Kenji Takeuchi,1 Takayuki Komatsu,1 and Junko Yokoo2

Department of Microbiology,1 Radioisotope Research Institute, Fukui Medical University School of Medicine, Yoshida-gun, Fukui 910-1193, Japan2

Received 23 September 2002/ Accepted 24 December 2002

Sendai virus (SeV) C protein functions as an interferon (IFN) antagonist and renders cells unresponsive to both alpha/beta IFN (IFN-{alpha}/ß) and IFN-{gamma}. We have recently found the physical association of the C protein with signal transducer and activator of transcription 1 (STAT1) in infected cells. However, involvement of the C-STAT1 interaction in the blockade of IFN signaling has remained unclear. We generated here a series of C mutant proteins that retained or lost the STAT1-binding capacity and examined their effects on IFN-{alpha} signaling. All of the C mutant proteins with no STAT1-binding capacity lost the ability to inhibit the IFN-{alpha} response. In contrast, the C mutant proteins retaining the STAT1-binding capacity suppressed IFN-{alpha}-stimulated tyrosine phosphorylation of both STAT2 and STAT1 to various degrees. Remarkably, their anti-IFN-{alpha} capacities correlated well with the inhibitory effect on phosphorylation of STAT2 rather than STAT1. In infected cells, the levels of tyrosine-phosphorylated (pY) STAT2 were below the detection level irrespective of duration of IFN-{alpha} stimulation, whereas the levels of pY-STAT1 strikingly increased after long-term IFN-{alpha} stimulation. These results suggest that the STAT2 activation process is a crucial target for the blockade of IFN-{alpha} signaling. An in vitro binding assay with extracts from (STAT1-deficient) U3A and (STAT1-expressing) U3A-ST1 cells suggested the requirement of STAT1 for the C-STAT2 interaction. Furthermore, expression of STAT1 enhanced the inhibitory effect of the C protein on STAT2 activation in U3A cells. The C protein thus appears to participate in the inhibitory process for STAT2 activation through the STAT1 interaction.

* Corresponding author. Mailing address: Department of Microbiology, Fukui Medical University School of Medicine, Shimoaizuki 23-3, Matsuoka-cho, Yoshida-gun, Fukui 910-1193, Japan. Phone: 81-776-61-8324. Fax: 81-776-61-8104. E-mail: bin{at}fmsrsa.fukui-med.ac.jp.

Journal of Virology, March 2003, p. 3360-3370, Vol. 77, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.6.3360-3370.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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