The P gene of Respirovirus encodes for P but also for a panel of accessory proteins by site-specific editing of P mRNA and usage of overlapping open reading frames (ORFs). In all Respirovirus except hPIV1, the co-transcriptional insertion of one G residue at an editing motif midway of P mRNA leads to the expression of a chimeric protein called V. The V proteins of bPIV3 and Sendai virus bind MDA5 and suppress double-stranded RNA-stimulated IFN-b production, thereby contributing to the virus evasion of host immune response [5] . Surprisingly in hPIV3, multiple stop codons localized downstream of the editing site prevent the normal expression of a full-length V protein. As a result, P mRNA molecules edited by the addition of one G residue encode for the 242 amino acid (AA)-long N-terminal residues of P followed by only six additional AA (see Materials and Methods and [6] ). But P mRNA molecules edited by the addition of five G residues encode for D, a protein exhibiting a large and specific C-terminal domain of unknown function ( Figure 1A ). Besides co-transcriptional edition, an overlapping ORF embedded in the first half of the P mRNA allows the expression of a single C protein (hPIV3 and bPIV3) or a nested set of four proteins called C9, C, Y1 and Y2 (Sendai virus and hPIV1). The C proteins of Sendai virus and hPIV1 have a high degree of sequence homology and have been studied in details. They are involved in the regulation of viral RNA synthesis [7, 8] , the inhibition of innate immune response [9] and potentially contribute to the budding of viral particles [10] [11] [12] . In particular, the C protein of Sendai virus both inhibits IFN-b production [13, 14] and blocks interferon signaling downstream of IFN-a/b and IFN-c receptors [15] [16] [17] . The C proteins of hPIV3 and bPIV3 only share ,35% of sequence homology with the C proteins of Sendai virus and hPIV1, but they have also been shown to target interferon expression and signaling [5, 18] . Although expression of the C protein of hPIV3 (hPIV3-C) is essential to virulence in vitro and in vivo [19] and explains hPIV3 ability to block IFN-a/b signaling [20] , host proteins that bind hPIV3-C remain unknown. (A) Organization of the gene P of hPIV3 that encodes for three proteins: P, D and C. Whereas conventional transcription and translation lead to the expression of the phosphoprotein P, co-transcriptional insertion of five G residues at the editing site by the virus RNA polymerase leads to the expression of a chimeric protein called D. Insertion of one G residue can also occur during transcription but two stop codons immediately downstream of the editing site prevent the expression of the protein V that is specific of Paramyxoviridae. The protein C is encoded by an overlapping opened reading frame (ORF) embedded in P mRNA. (B and C) HEK-293T cells were transfected with expression vectors encoding GST alone or fused to the C proteins of measles virus (MV-C), hPIV3 (hPIV3-C), or Nipah virus (Nipah-C), and tested for the interaction with endogenous STAT1 (B) or GRB2 (C). Total cell lysates were prepared 48 h post transfection (cell lysate; middle and lower panels), and copurifications of endogenous cellular proteins were assayed by pulldown using glutathione-sepharose beads (GST pull-down; upper panel). GST-tagged C proteins were detected by immunoblotting using anti-GST antibody, while endogenous STAT1 and GRB2 were detected with specific monoclonal antibodies. doi:10.1371/journal.ppat.1000587.g001