Direct Host Cell Membrane Membrane Fusion and Release of SARS-CoV-2 Nucleocapsid

Stable Identifier
Reaction [uncertain]
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
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SARS-CoV-2 virions attached to the host cell surface via a complex involving viral spike (S) protein and host angiotensin-converting enzyme 2 (ACE2) can directly fuse their membrane with the host cell membrane, releasing the uncoated virion nucleocapsid into the cytoplasm. The process starts with the spike protein undergoing cleavage by furin into S1/S2, followed by cleavage of S2 catalyzed by TMPRSS2, freeing the fusion peptide (FP) which mediates membrane fusion. 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).
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
21068237 A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry

Perlman, S, Shulla, A, Zhao, J, Gallagher, T, Heald-Sargent, T, Subramanya, G

J. Virol. 2011
21325420 Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response

Glowacka, I, Drosten, C, Niemeyer, D, He, Y, Bertram, S, Steffen, I, Müller, MA, Gnirss, K, Soilleux, E, Pöhlmann, S, Tsegaye, TS, Pfefferle, S, Allen, P, Schneider, H

J. Virol. 2011
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
15474033 Efficient assembly and release of SARS coronavirus-like particles by a heterologous expression system

Mortola, E, Roy, P

FEBS Lett. 2004
Catalyst Activity

serine-type endopeptidase activity of FURIN [plasma membrane]

serine-type endopeptidase activity of TMPRSS2 [plasma membrane]

Name Identifier Synonyms
COVID-19 DOID:0080600 2019 Novel Coronavirus (2019-nCoV), Wuhan seafood market pneumonia virus infection, 2019-nCoV infection, Wuhan coronavirus infection
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