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.

流感病毒感染是由病毒血凝素 (HA) 蛋白附着在宿主细胞表面的唾液酸受体上引发的。大多数病毒颗粒通过网格蛋白介导的内吞作用（CME）进入细胞。然而，尚不清楚病毒结合信号如何通过质膜传递从而触发 CME。在这里，我们使用 siRNA 筛选方法发现代谢型谷氨酸受体亚型 2 (mGluR2) 和钾钙激活通道亚家族 M α 1 (KCa1.1) 参与流感病毒 CME 的启动和完成。流感病毒HA直接与mGluR2相互作用，并将其作为内吞受体启动CME。 mGluR2 相互作用并激活 KCa1.1，导致 F-肌动蛋白聚合、网格蛋白包被凹坑成熟以及流感病毒 CME 的完成。重要的是，mGluR2 敲除小鼠对不同流感亚型的抵抗力明显强于野生型。因此，阻断 HA 和 mGluR2 相互作用可能是一种有前途的宿主导向抗病毒策略。