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Journal of Virology, August 2004, p. 8799-8811, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8799-8811.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

A Short Peptide at the Amino Terminus of the Sendai Virus C Protein Acts as an Independent Element That Induces STAT1 Instability

Dominique Garcin,1 Jean-Baptiste Marq,1 Fréderic Iseni,1 Stephen Martin,2 and Daniel Kolakofsky1*

Department of Microbiology and Molecular Medicine, University of Geneva School of Medicine, CH1211 Geneva, Switzerland,1 Division of Physical Biochemistry, National Institute of Medical Research, London NW7 1AA, United Kingdom2

Received 3 February 2004/ Accepted 6 April 2004

The Sendai virus C protein acts to dismantle the interferon-induced cellular antiviral state in an MG132-sensitive manner, in part by inducing STAT1 instability. This activity of C maps to the first 23 amino acids (C1-23) of the 204-amino-acid (aa)-long protein (C1-204). C1-23 was found to act as an independent viral element that induces STAT1 instability, since this peptide fused to green fluorescent protein (C1-23/GFP) is at least as active as C1-204 in this respect. This peptide also induces the degradation of C1-23/GFP and other proteins to which it is fused. Most of C1-204, and particularly its amino-terminal half, is predicted to be structurally disordered. C1-23 as a peptide was found to be disordered by circular dichroism, and the first 11 aa have a strong potential to form an amphipathic {alpha}-helix in low concentrations of trifluoroethanol, which is thought to mimic protein-protein interaction. The critical degradation-determining sequence of C1-23 was mapped by mutation to eight residues near its N terminus: 4FLKKILKL11. All the large hydrophobic residues of 4FLKKILKL11, plus its ability to form an amphipathic {alpha}-helix, were found to be critical for STAT1 degradation. In contrast, C1-23/GFP self-degradation did not require 8ILKL11, nor the ability to form an {alpha}-helix throughout this region. Remarkably, C1-23/GFP also stimulated C1-204 degradation, and this degradation in trans required the same peptide determinants as for STAT1. Our results suggest that C1-204 coordinates its dual activities of regulating viral RNA synthesis and counteracting the host innate antiviral response by sensing both its own intracellular concentration and that of STAT1.

* Corresponding author. Mailing address: Department of Microbiology and Molecular Medicine, University of Geneva School of Medicine, 11 Ave. de Champel, CH1211 Geneva, Switzerland. Phone: 41223795657. Fax: 41-223795702. E-mail: daniel.kolakofsky{at}medecine.unige.ch.

Journal of Virology, August 2004, p. 8799-8811, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8799-8811.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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