LAMR1 restricts Zika virus infection by attenuating the envelope protein ubiquitination

Zika virus (ZIKV) infection can cause severe neurological disorders, including Guillain–Barre syndrome and meningoencephalitis in adults and microcephaly in fetuses. Here, we reveal that laminin receptor 1 (LAMR1) is a novel host resistance factor against ZIKV infection. Mechanistically, we found that LAMR1 binds to ZIKV envelope (E) protein via its intracellular region and attenuates E protein ubiquitination through recruiting the deubiquitinase eukaryotic translation initiation factor 3 subunit 5 (EIF3S5). We further found that the conserved G282 residue of E protein is essential for its interaction with LAMR1. Moreover, a G282A substitution abolished the binding of E protein to LAMR1 and inhibited LAMR1-mediated E protein deubiquitination. Together, our results indicated that LAMR1 represses ZIKV infection through binding to E protein and attenuating its ubiquitination.