RT Journal Article
SR Electronic
T1 Opposing activities of IFITM proteins in SARS-CoV-2 infection
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.08.11.246678
DO 10.1101/2020.08.11.246678
A1 Guoli Shi
A1 Adam D. Kenney
A1 Elena Kudryashova
A1 Lizhi Zhang
A1 Luanne Hall-Stoodley
A1 Richard T. Robinson
A1 Dmitri S. Kudryashov
A1 Alex A. Compton
A1 Jacob S. Yount
YR 2020
UL http://biorxiv.org/content/early/2020/08/11/2020.08.11.246678.abstract
AB Interferon-induced transmembrane proteins (IFITMs) restrict infections by many viruses, but a subset of IFITMs enhance infections by specific coronaviruses through currently unknown mechanisms. Here we show that SARS-CoV-2 Spike-pseudotyped virus and genuine SARS-CoV-2 infections are generally restricted by expression of human IFITM1, IFITM2, and IFITM3, using both gain- and loss-of-function approaches. Mechanistically, restriction of SARS-CoV-2 occurred independently of IFITM3 S-palmitoylation sites, indicating a restrictive capacity that is distinct from reported inhibition of other viruses. In contrast, the IFITM3 amphipathic helix and its amphipathic properties were required for virus restriction. Mutation of residues within the human IFITM3 endocytosis-promoting YxxΦ motif converted human IFITM3 into an enhancer of SARS-CoV-2 infection, and cell-to-cell fusion assays confirmed the ability of endocytic mutants to enhance Spike-mediated fusion with the plasma membrane. Overexpression of TMPRSS2, which reportedly increases plasma membrane fusion versus endosome fusion of SARS-CoV-2, attenuated IFITM3 restriction and converted amphipathic helix mutants into strong enhancers of infection. In sum, these data uncover new pro- and anti-viral mechanisms of IFITM3, with clear distinctions drawn between enhancement of viral infection at the plasma membrane and amphipathicity-based mechanisms used for endosomal virus restriction. Indeed, the net effect of IFITM3 on SARS-CoV-2 infections may be a result of these opposing activities, suggesting that shifts in the balance of these activities could be coopted by viruses to escape this important first line innate defense mechanism.Competing Interest StatementThe authors have declared no competing interest.