FURIN Mediated SARS-CoV-2 Spike Protein Cleavage

Stable Identifier
R-HSA-9769949
Type
Reaction [transition]
Species
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
Compartment
plasma membrane
ReviewStatus
5/5
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FURIN Mediated SARS-CoV-2 Spike Protein Cleavage
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In a SARS-CoV-2 infection the cellular protease furin cleaves the spike protein at the S1/S2 site and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. The furin cleavage site promotes increased spike cleavage that has implications for pathogenesis (Hoffman et al. 2020; Johnson et al, 2021). Furin is associated with the plasma membrane of host cells and mediates the hydrolytic cleavage of SARS-CoV-2 Spike (S) protein associated with ACE2. Spike cleavage by furin is affected by O-glycosylations around the cleavage site at position 685-686. In particular the P681 mutation, which occurs in the SARS-CoV-2 alpha and delta variants, results in decreased O-glycosylation, increased furin cleavage, and increased syncytia formation which may contribute to increased viral infectivity (Zhang et al, 2021a).

Heparin binding to SARS-CoV-2 spike (S) effectively inhibits its cleavage into S1, S2 by furin. Unfractionated heparin (UFH) exhibits a higher furin inhibitory potency than the low-molecular-weight heparin (LMWH) (Paiardi et al, 2021). However, cleavage at the S1/S2 site occurs to some extent even if furin is absent, presumably due to the action of other proprotein convertases (Papa et al, 2021; Jaimes et al, 2020; reviewed by Takeda, 2022). Additionally it appears that, in the absence of furin-mediated priming of S, TMPRSS2 promotes the secretion of a shed form of ACE2 (sACE2) that favors cell-to-cell fusion (Essalmani et al, 2022).
Literature References
PubMed ID Title Journal Year
32512386 Proteolytic Cleavage of the SARS-CoV-2 Spike Protein and the Role of the Novel S1/S2 Site

Millet, JK, Jaimes, JA, Whittaker, GR

iScience 2020
33494095 Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis

Suthar, MS, Zhang, L, An, Z, Diamond, MS, Lee, B, Shi, PY, Weaver, SC, Debbink, K, Zhang, X, Vanderheiden, A, Winkler, ES, Popov, V, Ren, P, Menachery, VD, Muruato, A, Vu, M, Routh, AL, Freiberg, AN, Aguilar, P, Xie, X, Bailey, AL, Juelich, T, Ku, Z, Bopp, N, Plante, JA, Swetnam, D, Smith, JK, Schindewolf, C, Plante, KS, Lokugamage, KG, Kalveram, B, Johnson, BA, Zou, J

Nature 2021
34561887 Proteolytic activation of SARS-CoV-2 spike protein

Takeda, M

Microbiol Immunol 2022
32532959 The role of furin cleavage site in SARS-CoV-2 spike protein-mediated membrane fusion in the presence or absence of trypsin

Jiang, S, Lu, L, Liu, Z, Wang, Q, Su, S, Zhu, Y, Xia, S, Xu, W, Wang, X, Lan, Q

Signal Transduct Target Ther 2020
34929169 The binding of heparin to spike glycoprotein inhibits SARS-CoV-2 infection by three mechanisms

Wade, RC, Paiardi, G, Urbinati, C, Oreste, P, Richter, S, Rusnati, M

J Biol Chem 2022
33493182 Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion

James, LC, Papa, G, Luptak, J, McMahon, HT, Cattin-Ortolá, J, Albecka, A, Mallery, DL, Carter, A, Paul, D, Munro, S, Welch, LG, Goodfellow, IG

PLoS Pathog 2021
34732583 Furin cleavage of the SARS-CoV-2 spike is modulated by O-glycosylation

Samara, NL, Syed, ZA, Mann, M, Tabak, LA, Ten Hagen, KG, Tian, E, Reynolds, HM, Zeldin, DC, Zhang, L

Proc Natl Acad Sci U S A 2021
32362314 A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells

Pöhlmann, S, Hoffmann, M, Kleine-Weber, H

Mol. Cell 2020
35343766 Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity

Mapa, C, Jain, J, Susan-Resiga, D, Huynh, DN, Seidah, NG, Evagelidis, A, Delpal, A, Wilcoxen, K, Essalmani, R, Dallaire, F, Sutto-Ortiz, P, Laporte, M, Cohen, EA, Andréo, U, Decroly, E, Coutard, B, Derbali, RM, Nq Pham, T

J Virol 2022
Participants
Input
Output
Participates
as an event of
Catalyst Activity

serine-type endopeptidase activity of FURIN [plasma membrane]

Physical Entity
FURIN [plasma membrane] (Homo sapiens)
Activity
serine-type endopeptidase activity (GO:0004252)
This event is regulated
Negatively by
Regulator
Spike:heparin [extracellular region] (Severe acute respiratory syndrome coronavirus 2)
Disease
Name Identifier Synonyms
COVID-19 DOID:0080600 2019 Novel Coronavirus (2019-nCoV), Wuhan seafood market pneumonia virus infection, 2019-nCoV infection, Wuhan coronavirus infection
Authored
Stephan, R  (2022-03-23)
Reviewed
Gillespie, ME  (2022-05-10)
Created
Stephan, R  (2022-03-23)
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