TMPRSS2 Mediated SARS-CoV-2 Spike Protein Cleavage and Endocytosis

Stable Identifier
R-HSA-9694661
Type
Reaction [transition]
Species
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
Compartment
plasma membrane
ReviewStatus
5/5
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TMPRSS2 Mediated SARS-CoV-2 Spike Protein Cleavage and Endocytosis
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Transmembrane protease serine 2 (TMPRSS2), associated with the plasma membrane of the host cell, mediates the hydrolytic cleavage of SARS-CoV-2 Spike (S) protein component of the viral membrane-associate S3:M:E:encapsidated SARS coronavirus genomic RNA: 7a:O-glycosyl 3a tetramer complex associated with ACE2 (Xia et al, 2020; Bestle et al, 2020; Koch et al, 2021).

Neuropilin-1 (NRP1) is a receptor expressed in a broad range of cells from human organ systems including respiratory, urinary, digestive, reproductive, and immune systems. Specific cell lines from these organs are susceptible to SARS-CoV-2 infection. From these A549 (lung) and HRC45 (kidney) cells had a robust SARS‐CoV‐2 pseudovirus infection but weak levels of ACE2, and both expressed strong levels of NRP1 (Zhang et al, 2021). High levels of NRP1 were detected in the epithelial surface layer of the human respiratory and olfactory epithelium, with ACE2 hardly detectable in these tissues. Artificial additional NRP1 expression in Caco-2 and HEK-293T cells increased SARS-CoV-2 infection markedly (Cantuti-Castelvetri et al, 2020; Zhu et al, 2021). The TMPRSS2-cleaved SARS-CoV-2 spike glycoprotein fragment S1 binds NRP1, and selective NRP1 inhibitors reduced SARS-CoV-2 entry and infectivity in Caco-2 cell culture (Daly et al, 2020). Taken together, NRP1 appears to be the entry factor on NRP1-rich cells, and a weak entry factor on cells where ACE2 is present.

Several cell lines also have relatively higher levels of Hepatitis A virus cellular receptor 1 (kidney injury molecule-1, HAVCR1, KIM1, TIM1), a membrane protein upregulated upon kidney injury. Recombinant HAVCR1 blocked infection of both SARS‐CoV‐2 and SARS‐CoV pseudoviruses in a dose‐dependent fashion in one‐way ANOVA analysis albeit no significant difference was detected when the treated groups were compared with the untreated infected group (Zhang et al, 2021b). HAVCR1 binds to SARS-CoV-2 spike glycoprotein. Uptake of spike virosomes by lung and kidney epithelial cells that naturally express HAVCR1 was inhibited by anti-HAVCR1 antibodies and a HAVCR1 inhibitor (Mori et al, 2022; Yang et al, 2021).
Literature References
PubMed ID Title Journal Year
34324210 SARS-CoV-2 pseudovirus infectivity and expression of viral entry-related factors ACE2, TMPRSS2, Kim-1, and NRP-1 in human cells from the respiratory, urinary, digestive, reproductive, and immune systems

Zhang, F, Li, W, Feng, J, Ramos da Silva, S, Ju, E, Zhang, H, Chang, Y, Moore, PS, Guo, H, Gao, SJ

J Med Virol 2021
33082294 Neuropilin-1 is a host factor for SARS-CoV-2 infection

Daly, JL, Simonetti, B, Klein, K, Chen, KE, Williamson, MK, Antón-Plágaro, C, Shoemark, DK, Simón-Gracia, L, Bauer, M, Hollandi, R, Greber, UF, Horvath, P, Sessions, RB, Helenius, A, Hiscox, JA, Teesalu, T, Matthews, DA, Davidson, AD, Collins, BM, Cullen, PJ, Yamauchi, Y

Science 2020
32532959 The role of furin cleavage site in SARS-CoV-2 spike protein-mediated membrane fusion in the presence or absence of trypsin

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

Signal Transduct Target Ther 2020
34431042 Genome-wide CRISPR activation screen identifies candidate receptors for SARS-CoV-2 entry

Zhu, S, Liu, Y, Zhou, Z, Zhang, Z, Xiao, X, Liu, Z, Chen, A, Dong, X, Tian, F, Chen, S, Xu, Y, Wang, C, Li, Q, Niu, X, Pan, Q, Du, S, Xiao, J, Wang, J, Wei, W

Sci China Life Sci 2021
33082293 Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity

Cantuti-Castelvetri, L, Ojha, R, Pedro, LD, Djannatian, M, Franz, J, Kuivanen, S, van der Meer, F, Kallio, K, Kaya, T, Anastasina, M, Smura, T, Levanov, L, Szirovicza, L, Tobi, A, Kallio-Kokko, H, Österlund, P, Joensuu, M, Meunier, FA, Butcher, SJ, Winkler, MS, Mollenhauer, B, Helenius, A, Gokce, O, Teesalu, T, Hepojoki, J, Vapalahti, O, Stadelmann, C, Balistreri, G, Simons, M

Science 2020
32995803 KIM-1/TIM-1 is a Receptor for SARS-CoV-2 in Lung and Kidney

Mori, Y, Fink, C, Ichimura, T, Sako, K, Mori, M, Lee, NN, Aschauer, P, Padmanabha Das, KM, Hong, S, Song, M, Padera, RF, Weins, A, Lee, LP, Nasr, ML, Dekaban, GA, Dikeakos, JD, Bonventre, JV

medRxiv 2022
33493263 Kidney injury molecule-1 is a potential receptor for SARS-CoV-2

Yang, C, Zhang, Y, Zeng, X, Chen, H, Chen, Y, Yang, D, Shen, Z, Wang, X, Liu, X, Xiong, M, Chen, H, Huang, K

J Mol Cell Biol 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
34159616 TMPRSS2 expression dictates the entry route used by SARS-CoV-2 to infect host cells

Koch, J, Uckeley, ZM, Doldan, P, Stanifer, M, Boulant, S, Lozach, PY

EMBO J 2021
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
Negatively by
Regulator
TMPRSS2:TMPRSS2 inhibitors [plasma membrane] (Homo sapiens)
Positively by
Regulator
NRP1 [plasma membrane] (Homo sapiens)
Regulator
HAVCR1 [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
Gillespie, ME  (2020-09-09)
Reviewed
Acencio, ML  (2020-09-09)
Created
Cook, J  (2020-07-07)
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