Opposing activities of IFITM proteins in SARS-CoV-2 infection.
EMBO J
; 40(3): e106501, 2021 02 01.
Article
in English
| MEDLINE | ID: covidwho-1389834
ABSTRACT
Interferon-induced transmembrane proteins (IFITMs) restrict infections by many viruses, but a subset of IFITMs enhance infections by specific coronaviruses through currently unknown mechanisms. We show that SARS-CoV-2 Spike-pseudotyped virus and genuine SARS-CoV-2 infections are generally restricted by human and mouse IFITM1, IFITM2, and IFITM3, using gain- and loss-of-function approaches. Mechanistically, SARS-CoV-2 restriction occurred independently of IFITM3 S-palmitoylation, indicating a restrictive capacity 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 IFITM3 endocytosis-promoting YxxФ 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 increases plasma membrane fusion versus endosome fusion of SARS-CoV-2, attenuated IFITM3 restriction and converted amphipathic helix mutants into infection enhancers. In sum, we 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 SARS-CoV-2 restriction.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antigens, Differentiation
/
RNA-Binding Proteins
/
SARS-CoV-2
/
COVID-19
/
Membrane Proteins
Limits:
Animals
/
Humans
Language:
English
Journal:
EMBO J
Year:
2021
Document Type:
Article
Affiliation country:
EMBJ.2020106501
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