Cell membrane skeletal protein 4.1R participates in entry of Zika virus into cells

• Protein 4.1R may be involved in the process of Zika virus entering host cells. • The deletion of protein 4.1R will significantly reduce Zika virus titer and viral protein synthesis. • Protein 4.1R interacts with Axl/Zika virus envelope (E) protein to promote Zika entry. Zika virus (ZIKV) is a typical mosquito-borne flavivirus known to cause severe fetal microcephaly and adult Guillain-Barré syndrome. Currently, there are no specific drugs or licensed vaccines available for ZIKV infection, and further research is required to identify host cell proteins involved in the virus's life cycle. Viruses are known to use host cell membrane skeletal proteins, such as actin and spectrin, to complete cell entry, transportation, and release. Here, based on immunoprecipitation, the Axl and ZIKV envelope (E) protein were shown to interact with the cell membrane skeleton protein 4.1R. Furthermore, deletion of 4.1R significantly reduced virus titer and viral protein synthesis. Our study showed that 4.1R is an important host cell protein during ZIKV infection and may be involved in the process of viral entry into host cells.