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
plasma membrane
ReviewStatus
5/5
Locations in the PathwayBrowser
Expand all
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
S2 Cleavage by TMPRSS2 Exposes S2' Initiating Cell-Cell Fusion
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Nature 2020
Participants
Input
Output
Participates
as an event of
Catalyst Activity

serine-type endopeptidase activity of TMPRSS2 [plasma membrane]

Physical Entity
TMPRSS2 [plasma membrane] (Homo sapiens)
Activity
serine-type endopeptidase activity (GO:0004252)
This event is regulated
Positively by
Regulator
ANOs [plasma membrane] (Homo sapiens)
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
Cross References
Mondo
Authored
Stephan, R  (2022-03-25)
Reviewed
Gillespie, ME  (2022-05-10)
Created
Stephan, R  (2022-03-25)
Cite Us!