Zixin Ni#,Jinliang Wang#,Xiaofei Yu,Yifan Wang,Jingfei Wang,Xijun He,Chengjun Li,Guohua Deng,Jianzhong Shi,Huihui Kong,Yongping Jiang,Pucheng Chen,Xianying Zeng,Guobin Tian,Hualan Chen,Zhigao Bu

Nat Microbiol.2024 Jun 7.doi: 10.1038/s41564-024-01713-x. Online ahead of print.

Abstract

Influenza virus infection is initiated by the attachment of the viral haemagglutinin (HA) protein to sialic acid receptors on the host cell surface. Most virus particles enter cells through clathrin-mediated endocytosis (CME). However, it is unclear how viral binding signals are transmitted through the plasma membrane triggering CME. Here we found that metabotropic glutamate receptor subtype 2 (mGluR2) and potassium calcium-activated channel subfamily M alpha 1 (KCa1.1) are involved in the initiation and completion of CME of influenza virus using an siRNA screen approach. Influenza virus HA directly interacted with mGluR2 and used it as an endocytic receptor to initiate CME. mGluR2 interacted and activated KCa1.1, leading to polymerization of F-actin, maturation of clathrin-coated pits and completion of the CME of influenza virus. Importantly, mGluR2-knockout mice were significantly more resistant to different influenza subtypes than the wild type. Therefore, blocking HA and mGluR2 interaction could be a promising host-directed antiviral strategy.