Specific biochemical investigations are still required to decipher how hPIV3-C can both inhibit IFN-a/b signaling and enhance EGFR and MAPK/ERK pathway. When searching the literature for viral proteins that target GRB2, we found specific reports on NS5A from hepatitis C virus and ORF3 from hepatitis E virus [54, 55] . Although NS5A inhibits MAPK/ERK activation induced by exogenous EGF, ORF3 was described as an activator of MAPK/ERK pathway like hPIV3-C. Both NS5A and ORF3 exhibit a proline-rich motif (PXXP) to bind the Src homology 3 (SH3) domains of GRB2, but there is no such motif in hPIV3-C suggesting that other mechanisms mediate STAT1 and GRB2 binding. Interestingly, these two cellular proteins exhibit SH2 domains. Such domains typically bind a phosphorylated tyrosine residue in the context of a longer peptide motif within a target protein. Although there is no evidence that hPIV3-C becomes phosphorylated, we have tested hPIV3-C interaction with mutant STAT1 and GRB2 exhibiting SH2 domains disabled for the interaction with phosphotyrosine residues. These mutants were not affected for the interaction with hPIV3-C (data not shown). This suggests that hPIV3-C either binds distinct regions of STAT1 and GRB2, or interacts with a region of the SH2 domain that does not involve the phosphotyrosine binding site. Finally, our results also show that full-length hPIV3-C is required to modulate IFNa/b and MAPK/ERK pathways since AA 90-195 that bind STAT1 and GRB2 are unable to do so when expressed alone. Full-length hPIV3-C was also required to observe a localization at the cell membrane, suggesting a link with its activity. Interestingly, the N-terminal 23 residues of Sendai virus C protein act as a membrane targeting signal [56] . But the N-terminal residues of hPIV3-C (AA 1-89) were unable to do so, and sequence analysis did not show any conservation with the C protein of Sendai virus. Thus, hPIV3-C tertiary structure is apparently required to target this protein at the cell membrane. This specific localization could both sequester STAT1 to prevent the stimulation of IFN-target genes and contribute to the aggregation of GRB2-SOS complexes to enhance MAPK/ERK signaling [57] . Altogether, this suggests that hPIV3-C interaction with STAT1 and GRB2 represents a potential target for the development of antiviral molecules against hPIV3 and possibly other members of Respirovirus genus.