S2 Cleavage by TMPRSS2 Exposes S2' Initiating Cell-Cell Fusion

Stable Identifier
R-HSA-9770187
Type
Reaction [transition]
Species
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
Compartment
ReviewStatus
5/5
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SARS-CoV-2 fusion protein (S2', FP, fusion peptide) is a protein (458 aa) which is cleaved from the S2 fragment by TMPRSS2 and possibly other unknown host endopeptidases (Bestle et al, 2020; Navaratnarajah et al, 2021; reviewed by Takeda, 2022). S2' initiates membrane fusion by oligomerizing into an aggregated β-sheet conformation, especially when situated in cholesterol containing membrane regions. This conformation supports local membrane perturbations, a prerequisite for creation of point-like protrusions of membrane, leading to the formation of a fusion pore. Multiple membrane active regions of the Spike protein might be involved in membrane fusion in a concerted or synergistic fashion, see (Chakrabortya and Bhattacharjya, 2020) for review.



In SARS-CoV-2, inhibition of actin polymerization blocked fusion, consistent with a putative role for cortical actomyosin-generated mechanical forces in fusion pore formation. Membrane cholesterol is required for fusion but is delivered via a raft-independent mechanism; cholesterol present in the plasma membrane greatly enhanced viral-spoke association and membrane fusion (Sanders et al, 2021). Of all proteins in viruses that infect humans, SARS-CoV-2 spike features the highest cysteine content, and it appears palmitoylation (a non-enzymatic modification) of these cysteines is essential for its ability to initiate membrane fusion (Sanders et al, 2021; Nguyen et al, 2021; Li et al, 2022). Additionally it appears that Ca2+-activated TMEM6 family transmembrane transport proteins, in particular ubiquitous anoctamin-6 (ANO6, TMEM16F), are essential for cell-cell fusion. TMEM16 phospholipid scramblases translocate phospholipids bidirectionally between the plasma membrane leaflets which can serve as a fusion signal (Braga et al, 2021; Whitlock & Chernomordik, 2021).
Literature References
PubMed ID Title Journal Year
34528721 Palmitoylation of SARS-CoV-2 S protein is critical for S-mediated syncytia formation and virus entry

Lu, Y, Li, D, Zhang, L, Gao, S, Liu, Y

J Med Virol 2022
33051876 Syncytia formation by SARS-CoV-2-infected cells

Bruel, T, Guivel-Benhassine, F, Mouquet, H, Planas, D, Porrot, F, Rajah, MM, Buchrieser, J, Casartelli, N, van der Werf, S, Schwartz, O, Monel, B, Hubert, M, Dufloo, J, Planchais, C

EMBO J 2020
34561887 Proteolytic activation of SARS-CoV-2 spike protein

Takeda, M

Microbiol Immunol 2022
33310888 Spike glycoprotein and host cell determinants of SARS-CoV-2 entry and cytopathic effects

Sodroski, J, Wang, J, Ding, H, Wang, Q, Zhang, S, Nguyen, HT, Kappes, JC, Anang, S

J Virol 2020
32721790 Mechanistic insights of host cell fusion of SARS-CoV-1 and SARS-CoV-2 from atomic resolution structure and membrane dynamics

Chakraborty, H, Bhattacharjya, S

Biophys Chem 2020
33890572 SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation

Donlic, A, Padera, RF, Suzuki, S, Jumper, CC, Ploss, A, Holehouse, AS, Tamura, T, Bracha, D, Saeed, M, Levental, I, Castello-Serrano, I, Brangwynne, CP, Tavares, AH, Kim, H, Levy, BD, Ackerman, PJ, Sanders, DW, Kenney, D, Douam, F

Elife 2021
33827113 Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia

Rizzari, G, Barclay, WS, Neves, G, Bussani, R, Chiavacci, E, Ali, H, Malim, MH, Schneider, E, Secco, I, Goldhill, D, Giacca, M, Jiménez-Guardeño, JM, Collesi, C, Burrone, J, Braga, L, Shah, AM, Ortega-Prieto, AM, Penn, R, Arosio, D, Cannatà, A

Nature 2021
34613786 Highly Efficient SARS-CoV-2 Infection of Human Cardiomyocytes: Spike Protein-Mediated Cell Fusion and Its Inhibition

Cattaneo, R, Halfmann, PJ, Navaratnarajah, CK, Taye, B, Howell, KG, Schneider, JW, Christensen, TA, Barkhymer, A, Kawaoka, Y, Charlesworth, JE, Pease, DR

J Virol 2021
33581114 Flagging fusion: Phosphatidylserine signaling in cell-cell fusion

Whitlock, JM, Chernomordik, LV

J Biol Chem 2021
32703818 TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

Eickmann, M, Heindl, MR, Garten, W, Rohde, C, Bestle, D, Van Lam van, T, Stein, DA, Moulton, H, Dolnik, O, Pilgram, O, Klenk, HD, Limburg, H, Böttcher-Friebertshäuser, E, Hardes, K, Steinmetzer, T

Life Sci Alliance 2020
32942285 Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion

Roustan, C, Gamblin, SJ, Skehel, JJ, Rosenthal, PB, Martin, SR, Wrobel, AG, Benton, DJ, Xu, P

Nature 2020
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Participates
Catalyst Activity

serine-type endopeptidase activity of TMPRSS2 [plasma membrane]

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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
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