Piezo1 inhibition promoted MELK degradation and impeded influenza virus entry into host cells.

INTRODUCTION

The influenza virus continues to represent a persistent and significant challenge to public health worldwide. Viral entry into host cells is a critical initial step in the viral life cycle; however, the regulatory network of host factors involved in this process, particularly the role of Piezo-mechanosensitive elements, has not been fully elucidated.

OBJECTIVES

To determine the precise role of Piezo1 in respiratory epithelial cells during influenza virus infection and to validate the antiviral efficacy of targeting Piezo1 in vivo.

METHODS

This study elucidated the molecular mechanism of Piezo1-MELK axis-mediated influenza virus entry into host cells via gene editing, proteomics, and IP-MS screening, and verified the anti-influenza effect of Piezo1 targeting in knockout mouse models.

RESULTS

We found that Piezo-type mechanosensitive ion channel component 1 (Piezo1) is crucial for IAV entry. Mechanistically, Piezo1 stabilizes the maternal embryonic leucine zipper kinase (MELK), which we identify as a novel IAV endocytic receptor that binds viral hemagglutinin (HA). Additionally, the influenza virus, through MELK, interacted with Piezo1, leading to calcium influx and F-actin polymerization, which drive influenza virus entry. Importantly, specifically inhibiting or knocking out Piezo1 in the lungs of mice significantly improves survival during influenza virus infection.

CONCLUSION

This study reveals a Piezo1-MELK axis coordinating IAV attachment and endocytosis, suggesting that targeting Piezo1 could be a promising host-directed antiviral strategy.