Tyrosine kinase LYN restricts the replication and virulence of influenza A virus by directly phosphorylating viral nucleoprotein

作者：Junwen Liu, Jia-Xin Huang, Qian Wang, Yan-Li Wei, Le-Bin Han, Xin Li, Caoqi Lei, G. Deng, Hua-Lan Chen, Qi-Yun Zhu, Shuai Xu · 发表于：mBio · 年份：2026 · DOI：10.1128/mbio.03759-25 · 研究领域：Medicine

ABSTRACT The continuous antigenic shift and drift of influenza A virus (IAV) result in the emergence of novel strains and drug resistance. Accordingly, it is urgent to develop novel antiviral drugs that target host factors. Here, we revealed that tyrosine kinase LYN (Lck/Yes-related novel protein tyrosine kinase) interacts directly with nucleoprotein (NP) and reduces the replication and virulence of IAV in vitro and in vivo, in a kinase-dependent manner. By directly catalyzing the tyrosine phosphorylation of NP at Y10/40/97 sites, LYN impairs the interaction of NP with viral RNA and polymerase proteins, as well as the oligomerization of NP, and thus negatively modulates the assembly of the viral ribonucleoprotein complex. The NPY10/40/97F mutation significantly increases the pathogenicity of IAV in mice. Furthermore, the LYN-specific agonist MLR-1023 showed promising therapeutic effects against IAV. Collectively, our findings suggest that LYN is a novel host kinase restricting IAV replication, and a promising target for anti-influenza drug development. IMPORTANCE The nucleoprotein (NP) of influenza A virus (IAV) is a highly conserved, multifunctional, and the most abundant viral protein in infected cells, which makes NP a promising target for the development of anti-influenza drugs. Phosphorylation plays a crucial role in the stability and functionality of NP. However, few kinases have been identified that directly phosphorylate NP. In this study, LYN (Lck/Yes-related novel p...