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

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Abstract
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 (C 1-23 ) of the 204-amino-acid (aa)-long protein (C 1-204 ). C 1-23 was found to act as an independent viral element that induces STAT1 instability, since this peptide fused to green fluorescent protein (C 1-23 /GFP) is at least as active as C 1-204 in this respect. This peptide also induces the degradation of C 1-23 /GFP and other proteins to which it is fused. Most of C 1-204 , and particularly its amino-terminal half, is predicted to be structurally disordered. C 1-23 as a peptide was found to be disordered by circular dichroism, and the first 11 aa have a strong potential to form an amphipathic α-helix in low concentrations of trifluoroethanol, which is thought to mimic protein-protein interaction. The critical degradation-determining sequence of C 1-23 was mapped by mutation to eight residues near its N terminus: 4 FLKKILKL 11 . All the large hydrophobic residues of 4 FLKKILKL 11 , plus its ability to form an amphipathic α-helix, were found to be critical for STAT1 degradation. In contrast, C 1-23 /GFP self-degradation did not require 8 ILKL 11 , nor the ability to form an α-helix throughout this region. Remarkably, C 1-23 /GFP also stimulated C 1-204 degradation, and this degradation in trans required the same peptide determinants as for STAT1. Our results suggest that C 1-204 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.