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Journal of Virology, July 2004, p. 7443-7454, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7443-7454.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Characterization of the Amino Acid Residues of Sendai Virus C Protein That Are Critically Involved in Its Interferon Antagonism and RNA Synthesis Down-Regulation

Atsushi Kato,1* Case Cortese-Grogan,2 Sue A. Moyer,2 Fumihiro Sugahara,3 Takemasa Sakaguchi,3 Toru Kubota,1 Noriyuki Otsuki,1 Masayoshi Kohase,1 Masato Tashiro,1 and Yoshiyuki Nagai4

Department of Virology 3, National Institute of Infectious Diseases, Musashi-Murayama, Tokyo 208-0011,1 Department of Virology, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima 734-8551,3 Toyama Institute of Health, Kosugi-machi, Toyama 939-0363, Japan,4 Department of Molecular Genetics and Microbiology, University of Florida, College of Medicine, Gainesville, Florida 326102

Received 12 January 2004/ Accepted 25 February 2004

Sendai virus (SeV) encodes two accessory proteins, V and C, in the alternative reading frames in the P gene that are accessed transcriptionally (V) or translationally (C). The C protein is expressed as a nested set of four C-coterminal proteins, C', C, Y1, and Y2, that use different initiation codons. Using HeLa cell lines constitutively expressing the various C proteins, we previously found that the smallest (the 175-residue Y2) of the four C proteins was fully capable of counteracting the antiviral action of interferons (IFNs) and inhibiting viral RNA synthesis and that the C-terminal half of 106 residues was sufficient for both of these inhibitory functions (A. Kato et al., J. Virol. 75:3802-3810, 2001, and A. Kato et al., J. Virol. 76:7114-7124, 2002). Here, we further generated HeLa cell lines expressing the mutated C (Cm) proteins with charged amino acids substituted for alanine residues at either positions 77 and 80; 114 and 115; 139 and 142; 151, 153, and 154; 156; or 173, 175, and 176. We found that only the mutations at positions 151, 153, and 154 abolished IFN antagonism. All the Cm proteins lost the ability to bind with STAT1 under our assay conditions, regardless of their ability to inhibit IFN signaling. On the other hand, the Cm proteins that altered the tyrosine phosphorylation and dephosphorylation of STAT1 and STAT2 always retained IFN antagonism. Thus, the abnormality of phosphorylation or dephosphorylation appeared to be a cause of the IFN antagonism by SeV C. Regarding viral RNA synthesis inhibition, all mutants but the mutant with replacements at positions 114 and 115 greatly reduced the inhibitory activity, indicating that anti-RNA synthesis by the C protein is governed by amino acids scattered across its C-terminal half. Thus, amino acid sequence requirements differ greatly between IFN antagonism and RNA synthesis inhibition. In addition, we confirmed that another SeV accessory protein, V, does not antagonize IFN.

* Corresponding author. Mailing address: Department of Virology 3, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashi-Murayama, Tokyo 208-0011, Japan. Phone: 81 42 561 0711, ext. 530. Fax: 81 42 567 5631. E-mail: akato{at}nih.go.jp.

Journal of Virology, July 2004, p. 7443-7454, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7443-7454.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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