FKBP8 inhibits influenza a virus infection by degrading viral M2 protein in lysosomes

knockdown/knockout enhanced viral susceptibility. Mechanistically, FKBP8 interacted with M2 from diverse IAV strains via high-affinity binding between its tetratricopeptide repeat (TPR) domain and the LC3-interacting region (LIR) of M2, inhibiting viral entry. Importantly, FKBP8 mediated M2 degradation through the lysosomal pathway, not via translational inhibition, as shown by cycloheximide and lysosomal inhibitor (BafA1 and CQ) experiments. FKBP8 recruited RAB7A and LAMP1 to form a FKBP8-RAB7A-LAMP1-M2 complex, facilitating M2 transport to lysosomes. Additionally, FKBP8 interacted with envelope proteins of other enveloped RNA viruses, suggesting broad-spectrum antiviral potential. Our findings reveal FKBP8 as a conserved IAV restriction factor and its mechanism, providing insights for antiviral drug development.