Avian influenza viruses inhibit the major cellular signalling integrator c‐ A bl

Summary The non‐structural protein 1 ( NS 1) of influenza A viruses ( IAV ) encodes several src homology ( SH ) binding motifs (bm) (one SH 2bm, up to two SH 3bm), which mediate interactions with host cell proteins. In contrast to NS 1 of human IAV , NS 1 of avian strains possess the second SH 3bm ( SH 3( II )bm) consensus sequence. Since our former studies demonstrated an NS 1– CRK interaction, mediated by this motif, here, we addressed the regulatory properties of this SH 3bm for cellular signalling. Initially, we observed a reduced basal CRK phosphorylation upon infection with avian IAV harbouring an NS 1 with an SH 3( II )bm in contrast to human IAV . Reduced activity of the tyrosine kinase c‐ A bl was identified to be responsible for reduced CRK phosphorylation. Further, binding of NS 1 to c‐ A bl was determined, and mutational manipulation of the SH 3( II )bm illustrated the necessity of this motif for c‐ A bl inhibition. Interestingly, A bl kinase inhibition resulted in impaired avian IAV propagation and pathogenicity and mutational analysis linked the pronounced inhibition of c‐ A bl to cytopathogenic cell alterations upon avian IAV infections. Taken together, NS 1 proteins of avian IAV interfere with the kinase activity of c‐ A bl, a major cellular signalling integrator that controls multiple signalling processes and cell fate regulations apparently including IAV infections.