The Polybasic Cleavage Site in SARS-CoV-2 Spike Modulates Viral Sensitivity to Type I Interferon and IFITM2.
IFITM2
SARS-CoV-2
furin cleavage
innate immunity
spike
type 1 interferon
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
12 04 2021
12 04 2021
Historique:
received:
19
12
2020
accepted:
03
02
2021
pubmed:
11
2
2021
medline:
20
4
2021
entrez:
10
2
2021
Statut:
epublish
Résumé
The cellular entry of severe acute respiratory syndrome-associated coronaviruses types 1 and 2 (SARS-CoV-1 and -2) requires sequential protease processing of the viral spike glycoprotein. The presence of a polybasic cleavage site in SARS-CoV-2 spike at the S1/S2 boundary has been suggested to be a factor in the increased transmissibility of SARS-CoV-2 compared to SARS-CoV-1 by facilitating maturation of the spike precursor by furin-like proteases in the producer cells rather than endosomal cathepsins in the target. We investigate the relevance of the polybasic cleavage site in the route of entry of SARS-CoV-2 and the consequences this has for sensitivity to interferons (IFNs) and, more specifically, the IFN-induced transmembrane (IFITM) protein family that inhibit entry of diverse enveloped viruses. We found that SARS-CoV-2 is restricted predominantly by IFITM2, rather than IFITM3, and the degree of this restriction is governed by route of viral entry. Importantly, removal of the cleavage site in the spike protein renders SARS-CoV-2 entry highly pH and cathepsin dependent in late endosomes, where, like SARS-CoV-1 spike, it is more sensitive to IFITM2 restriction. Furthermore, we found that potent inhibition of SARS-CoV-2 replication by type I but not type II IFNs is alleviated by targeted depletion of IFITM2 expression. We propose that the polybasic cleavage site allows SARS-CoV-2 to mediate viral entry in a pH-independent manner, in part to mitigate against IFITM-mediated restriction and promote replication and transmission. This suggests that therapeutic strategies that target furin-mediated cleavage of SARS-CoV-2 spike may reduce viral replication through the activity of type I IFNs.
Identifiants
pubmed: 33563656
pii: JVI.02422-20
doi: 10.1128/JVI.02422-20
pmc: PMC8104117
pii:
doi:
Substances chimiques
IFITM2 protein, human
0
Interferon Type I
0
Membrane Proteins
0
Spike Glycoprotein, Coronavirus
0
spike protein, SARS-CoV-2
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Medical Research Council
ID : MC_PC_19041
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S000844/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_15068
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_14105
Pays : United Kingdom
Informations de copyright
Copyright © 2021 Winstone et al.
Références
Science. 2020 Nov 13;370(6518):856-860
pubmed: 33082293
J Virol. 2020 Nov 9;94(23):
pubmed: 32938761
Science. 2020 Nov 13;370(6518):861-865
pubmed: 33082294
Nat Med. 2020 Apr;26(4):450-452
pubmed: 32284615
mBio. 2020 Oct 16;11(5):
pubmed: 33067384
Retrovirology. 2017 Nov 21;14(1):53
pubmed: 29162141
Nat Rev Microbiol. 2015 Jul;13(7):403-13
pubmed: 25915633
PLoS One. 2012;7(11):e49265
pubmed: 23166625
J Biol Chem. 2012 Jun 1;287(23):19631-41
pubmed: 22511783
Cell Rep. 2020 Oct 6;33(1):108234
pubmed: 32979938
J Virol. 2017 May 12;91(11):
pubmed: 28356532
Front Immunol. 2020 Jun 10;11:1372
pubmed: 32595654
Annu Rev Virol. 2019 Sep 29;6(1):567-584
pubmed: 31283436
Nature. 2020 Aug;584(7821):463-469
pubmed: 32717743
Elife. 2020 Oct 28;9:
pubmed: 33112230
Cell Microbiol. 2014 Jul;16(7):1080-93
pubmed: 24521078
Cell. 2020 Apr 16;181(2):271-280.e8
pubmed: 32142651
Cell Host Microbe. 2020 Dec 9;28(6):867-879.e5
pubmed: 33271067
J Virol. 1992 Nov;66(11):6547-54
pubmed: 1404602
PLoS Pathog. 2011 Jan 06;7(1):e1001258
pubmed: 21253575
PLoS Pathog. 2021 Jan 21;17(1):e1009233
pubmed: 33476327
Curr Protoc Microbiol. 2020 Jun;57(1):ecpmc105
pubmed: 32475066
Cell Rep. 2020 Jul 7;32(1):107863
pubmed: 32610043
Genome Med. 2020 Jul 28;12(1):68
pubmed: 32723359
Mol Cell. 2020 May 21;78(4):779-784.e5
pubmed: 32362314
J Biol Chem. 2014 Apr 25;289(17):11986-11992
pubmed: 24627473
Annu Rev Virol. 2014 Nov 1;1:261-283
pubmed: 25599080
Cytokine. 2021 Jan;137:155354
pubmed: 33113474
J Virol. 2013 Dec;87(24):13321-9
pubmed: 24089552
Cell Host Microbe. 2016 Oct 12;20(4):429-442
pubmed: 27640936
PLoS Pathog. 2011 Oct;7(10):e1002337
pubmed: 22046135
Front Microbiol. 2019 Jan 08;9:3228
pubmed: 30687247
J Biol Chem. 2020 Oct 9;295(41):13958-13964
pubmed: 32587093
Front Immunol. 2018 Jan 04;8:1853
pubmed: 29354117
EMBO J. 2021 Feb 1;40(3):e106501
pubmed: 33270927
Science. 2020 Aug 7;369(6504):706-712
pubmed: 32527925
Science. 2020 Oct 23;370(6515):
pubmed: 32972996
MethodsX. 2015 Oct 13;2:379-84
pubmed: 26587388
Nat Struct Mol Biol. 2020 Aug;27(8):763-767
pubmed: 32647346
Int Immunopharmacol. 2021 Jan;90:107171
pubmed: 33221168
Cell. 2009 Dec 24;139(7):1243-54
pubmed: 20064371
EMBO J. 2020 Dec 1;39(23):e106267
pubmed: 33051876
J Virol. 2020 Aug 17;94(17):
pubmed: 32571797
Nature. 2020 Mar;579(7798):265-269
pubmed: 32015508
Traffic. 2016 Sep;17(9):997-1013
pubmed: 27219333