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PLC‐gamma1 signaling plays a subtype‐specific role in postbinding cell entry of influenza A virus (LB258)

Host signaling pathways and cellular proteins play important roles in the influenza viral life cycle and can serve as antiviral targets. In this study (Zhu, et al., 2014, J. Virol.), we report the engagement of host phosphoinositide‐specific phospholipase gamma 1 (PLC‐gamma1) in mediating cell entry of influenza virus H1N1 but not H3N2 subtype. Both PLC‐gamma1‐specific inhibitor and short hairpin RNA (shRNA) strongly suppress the replication of H1N1 but not H3N2 viruses in cell culture, suggesting that PLC‐gamma1 plays an important subtype‐specific role in the influenza viral life cycle. Further analyses demonstrate that PLC‐gamma1 activation is required for viral postbinding cell entry. In addition, H1N1, but not H3N2, infection leads to the phosphorylation of PLC‐gamma1 at Ser 1248 immediately after infection and independent of viral replication. We have further shown that H1N1‐induced PLC‐gamma1 activation is downstream of epidermal growth factor receptor (EGFR) signaling. Interestingly, both H1N1 and H3N2 infections activate EGFR, but only H1N1 infection leads to PLC‐γ1 activation. In summary, we have identified for the first time the subtype‐specific interplay of host PLC‐gamma1 signaling and H1N1 virus that is critical for viral uptake early in the infection. This is the latest study in our series of recent publications that reveal novel insights into how influenza virus interacts with the cellular signaling network (Zhu, et al., 2014 J. Virol., Kumar, et al., 2011 J. Virol., 2011 Antimicrobial Agents Chemother., 2008 J. Virol.).