Impact Factor:14.5

DOI number:10.1002/advs.202309477

Affiliation of Author(s):华中农业大学

Journal:Advanced Science

Key Words:Influenza virus, vRNP nuclear export, NEP S-S-S motif phosphorylation, vRNP nuclear export, ATM, CK2

Abstract:The phosphorylation of three highly conserved serine residues S23, S24, and S25 (S-S-S motif) has been previously identified in NEP of influenza virus. However, it remains obscure whether and how this motif regulates the vRNPs nuclear export. Here we generated the influenza A H5N6 viruses harboring NEP S23C, S24L, or S25L, allowing to impair the phosphorylation on these sites without mutating viral NS1 protein. We found these mutations significantly inhibited vRNPs nuclear export, decreased viral infectivity and attenuated virulence in mice. In addition, inhibition or knockout of ATM or CK2, two predicated Ser/Thr protein kinases that phosphorylate the S-S-S motif, impedes vRNP nuclear export and virus replication in cells and reduces the virulence in vivo. Moreover, treatment of NEP peptide mimics containing the S-S-S motif to competitively block NEP binding to the kinases reduces influenza virus replication in cells and mice. However, neither the inhibitors above nor the NEP peptide mimics significantly inhibit the replication of H5N6-DDD mutant, indicating phosphorylation of S-S-S motif is required for the vRNP nuclear export. Our studies contribute to a better understanding of the mechanism by which NEP regulates vRNP nuclear export and provides novel insights into antiviral targets against influenza A and B viruses.

Indexed by:Journal paper

Translation or Not:no

Date of Publication:2024-11-22

Included Journals:SCI