Inhibition of IFN-alpha/beta signaling by two discrete peptides within measles virus V protein that specifically bind STAT1 and STAT2.
The V protein of measles virus (MV-V) is a potent inhibitor of IFN-alpha/beta signaling pathway. We previously reported that when physically dissociated, the N-terminal and C-terminal regions of MV-V (PNT and VCT, respectively) could independently impair signal transduction. The PNT region inhibited IFN-alpha/beta signaling by interacting with at least two components of this pathway: Jak1 and STAT1. Here we report a direct interaction between the VCT of MV-V and STAT2, a third component of IFN-alpha/beta transduction machinery. This interaction with STAT2 is carried by the cysteine-constrained peptide of 49 amino acids localized in the VCT region, and is essential to the inhibition of IFN-alpha/beta signaling. In parallel, we also mapped STAT1 binding site in the PNT region and identified a minimal peptide of only 11 amino acids. IFN-alpha/beta signaling was impaired in human cells treated with this MV-V peptide fused to a cell-penetrating sequence. Finally, we show that signaling downstream of IFN-lambda, a recently identified cytokine that also relies on STAT1, STAT2 and Jak1 to transduce, is blocked by MV-V. Altogether, our results illustrate how a single viral protein has evolved to achieve a robust inhibition of the antiviral response by interacting with several signaling molecules.
Caignard
Grégory
G
Laboratoire de Génomique Virale et Vaccination, CNRS URA 3015, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France.
Bouraï
Mehdi
M
Jacob
Yves
Y
Tangy
Frédéric
F
Vidalain
Pierre-Olivier
PO
D000595:Amino Acid Sequence; D002460:Cell Line; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors*; D016899:Interferon-beta / Q000037:antagonists & inhibitors*; D008459:Measles virus / Q000276:immunology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050795:STAT2 Transcription Factor / Q000378:metabolism*; D016415:Sequence Alignment; D014764:Viral Proteins / Q000378:metabolism*
D016898:Interferon-alpha; D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; C069181:V protein, measles virus; D014764:Viral Proteins; D016899:Interferon-beta