TMPRSS2
| TMPRSS2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | TMPRSS2, PP9284, PRSS10, transmembrane protease, serine 2, transmembrane serine protease 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 602060; MGI: 1354381; HomoloGene: 4136; GeneCards: TMPRSS2; OMA:TMPRSS2 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Transmembrane protease, serine 2 is an enzyme that in humans is encoded by the TMPRSS2 gene.[5][6][7] It belongs to the TMPRSS family of proteins, whose members are transmembrane proteins which have a serine protease activity.[8] The TMPRSS2 protein is found in high concentration in the cell membranes of epithelial cells of the lung and of the prostate, but also in the heart, liver and gastrointestinal tract.[8]
Mutations of the TMPRSS2 gene are often involved in prostate cancer. Several viruses, including SARS-CoV-2, use the protease activity of the TMPRSS2 protein in the process of entering cells.[8]
Function
[edit]The TMPRSS2 gene encodes a protein that belongs to the serine protease family. The encoded protein contains a type II transmembrane domain, a low density lipoprotein receptor class A domain, a scavenger receptor cysteine-rich domain and a protease domain. Serine proteases are known to be involved in many physiological and pathological processes. This gene is up-regulated by androgenic hormones in prostate cancer cells and down-regulated in androgen-independent prostate cancer tissue. The protease domain of this protein is thought to be cleaved and secreted into cell media after autocleavage.[6] TMPRSS2 participates in proteolytic cascades necessary for normal physiological function of the prostate.[7] Gene knockout mice lacking TMPRSS2 show no abnormalities.[9]
Structure
[edit]
As a type II transmembrane protease, TMPRSS2 consists of an intracellular N-terminal domain, a transmembrane domain, a stem region that extends extracellularly and a C-terminal domain that catalyzes its serine protease (SP) activity.[12] This serine protease activity is orchestrated by a catalytic triad containing the residues His296, Asp345, and Ser441.[12][10] This noted catalytic triad is typically responsible for the cleaving of basic amino acid residues (lysine or arginine residues)— consistent with what is observed in the S1/S2 cleavage site found in SARS-CoV-2.[12] A notable domain in the stem region that has been examined through mutational analysis is the low density lipoprotein receptor class A domain (LDLRA).[12] Experimental evidence suggests that this domain likely participates in enzymatic activity of the protein and has been examined alongside another motif in the stem region: the scavenger receptor cysteine-rich domain (SRCR).[12] This domain may be implicated in the binding of extracellular molecules and other nearby cells.[13][14] Interestingly, SRCR may have a role in overall proteolytic activity of the protein, which could lead to implications on the overall virulence of SARS-CoV-2.[15][12][16]
Clinical significance
[edit]In prostate cancer
[edit]TMPRSS2 protein's function in prostate carcinogenesis relies on overexpression of ETS transcription factors, such as ERG and ETV1, through gene fusion. TMPRSS2-ERG fusion gene is the most frequent, present in 40% - 80% of prostate cancers in humans. ERG overexpression contributes to development of androgen-independence in prostate cancer through disruption of androgen receptor signaling.[17]
Coronaviruses
[edit]Some coronaviruses, e.g. SARS-CoV-1, MERS-CoV, and SARS-CoV-2 (although less well by the omicron variant[18]), are activated by TMPRSS2 and can thus be inhibited by TMPRSS2 inhibitors.[19][20] SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming.[21]
Cleavage of the SARS-CoV-2 S2 spike protein required for viral entry into cells can be accomplished by proteases TMPRSS2 located on the cell membrane, or by cathepsins (primarily cathepsin L) in endolysosomes.[22] Hydroxychloroquine inhibits the action of cathepsin L in endolysosomes, but because cathepsin L cleavage is minor compared to TMPRSS2 cleavage, hydroxychloroquine does little to inhibit SARS-CoV-2 infection.[22]
The enzyme Adam17 has similar ACE2 cleavage activity as TMPRSS2, but by forming soluble ACE2, Adam17 may actually have the protective effect of blocking circulating SARS‑CoV‑2 virus particles.[23] By not releasing soluble ACE2, TMPRSS2 cleavage is more harmful.[23]
A TMPRSS2 inhibitor such as camostat approved for clinical use blocked entry and might constitute a treatment option.[20][22] Another experimental candidate as a TMPRSS2 inhibitor for potential use against both influenza and coronavirus infections in general, including those prior to the advent of COVID-19, is the over-the-counter (in most countries) mucolytic cough medicine bromhexine,[24] which is also being investigated as a possible treatment for COVID-19 itself as well.[25] The fact that TMPRSS2 has no known irreplaceable function makes it a promising target for preventing SARS-CoV-2 virus transmission.[9]
The fact that severe illness and death from Sars-Cov-2 is more common in males than females, and that TMPRSS2 is expressed several times more highly in prostate epithelium than any tissue, suggests a role for TMPRSS2 in the gender difference.[26][27] Prostate cancer patients receiving androgen deprivation therapy have a lower risk of SARS-CoV-2 infection than those not receiving that therapy.[26][27]
Inhibitors
[edit]Camostat is an inhibitor of the serine protease activity of TMPRSS2. It is used to treat pancreatitis and reflux esophagitis.[28] It was found not to be effective against COVID-19.[29] A novel inhibitor of TMPRSS2 (N-0385) has been found to be effective against SARS-CoV-2 infection in cell and animal models.[30]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000184012 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000385 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE (September 1997). "Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3". Genomics. 44 (3): 309–320. doi:10.1006/geno.1997.4845. PMID 9325052.
- ^ a b "Entrez Gene: TMPRSS2 transmembrane protease, serine 2".
- ^ a b "UniProt Protein: TMPS2_HUMAN transmembrane protease".
- ^ a b c Thunders M, Delahunt B (December 2020). "Gene of the month: TMPRSS2 (transmembrane serine protease 2)". Journal of Clinical Pathology. 73 (12): 773–776. doi:10.1136/jclinpath-2020-206987. PMC 7470178. PMID 32873700.
- ^ a b Sarker J, Das P, Sarker S, Roy AK, Momen AZ (2021). "A Review on Expression, Pathological Roles, and Inhibition of TMPRSS2, the Serine Protease Responsible for SARS-CoV-2 Spike Protein Activation". Scientifica. 2021: 2706789. doi:10.1155/2021/2706789. PMC 8313365. PMID 34336361.
- ^ a b c Fraser BJ, Beldar S, Seitova A, Hutchinson A, Mannar D, Li Y, et al. (September 2022). "Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation". Nature Chemical Biology. 18 (9): 963–971. doi:10.1038/s41589-022-01059-7. PMID 35676539.
- ^ "Supplemental Information 4: UCSF Chimera". doi:10.7717/peerj.4593/supp-4.
{{cite web}}: Missing or empty|url=(help) - ^ a b c d e f Wettstein L, Kirchhoff F, Münch J (January 2022). "The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment". International Journal of Molecular Sciences. 23 (3): 1351. doi:10.3390/ijms23031351. PMC 8836196. PMID 35163273.
- ^ Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE (September 1997). "Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3". Genomics. 44 (3): 309–320. doi:10.1006/geno.1997.4845. PMID 9325052.
- ^ Wettstein L, Kirchhoff F, Münch J (January 2022). "The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment". International Journal of Molecular Sciences. 23 (3): 1351. doi:10.3390/ijms23031351. PMC 8836196. PMID 35163273.
- ^ Guipponi M, Antonarakis SE, Scott HS (January 2008). "TMPRSS3, a type II transmembrane serine protease mutated in non-syndromic autosomal recessive deafness". Frontiers in Bioscience. 13 (13): 1557–1567. doi:10.2741/2780. PMID 17981648.
- ^ Afar DE, Vivanco I, Hubert RS, Kuo J, Chen E, Saffran DC, et al. (February 2001). "Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia". Cancer Research. 61 (4): 1686–1692. PMID 11245484.
- ^ Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, et al. (May 2010). "An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression". Cancer Cell. 17 (5): 443–454. doi:10.1016/j.ccr.2010.03.018. PMC 2874722. PMID 20478527.
- ^ Meng B, Abdullahi A, Ferreira IA, Goonawardane N, Saito A, Kimura I, et al. (March 2022). "Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity". Nature. 603 (7902): 706–714. Bibcode:2022Natur.603..706M. doi:10.1038/s41586-022-04474-x. PMC 8942856. PMID 35104837.
- ^ Huggins DJ (November 2020). "Structural analysis of experimental drugs binding to the SARS-CoV-2 target TMPRSS2". Journal of Molecular Graphics & Modelling. 100: 107710. doi:10.1016/j.jmgm.2020.107710. PMC 7417922. PMID 32829149.
- ^ a b Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. (April 2020). "SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor". Cell. 181 (2): 271–280.e8. doi:10.1016/j.cell.2020.02.052. PMC 7102627. PMID 32142651.
- Lay summary in: "Preventing spread of SARS coronavirus-2 in humans". German Primate Center (Press release). March 5, 2020.
- ^ Rahman N, Basharat Z, Yousuf M, Castaldo G, Rastrelli L, Khan H (May 2020). "Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2)". Molecules. 25 (10): 2271. doi:10.3390/molecules25102271. PMC 7287752. PMID 32408547.
- ^ a b c Jackson CB, Farzan M, Chen B, Choe H (January 2022). "Mechanisms of SARS-CoV-2 entry into cells". Nature Reviews. Molecular Cell Biology. 23 (1): 3–20. doi:10.1038/s41580-021-00418-x. PMC 8491763. PMID 34611326.
- ^ a b Zipeto D, Palmeira JD, Argañaraz GA, Argañaraz ER (2020). "ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19". Frontiers in Immunology. 11: 576745. doi:10.3389/fimmu.2020.576745. PMC 7575774. PMID 33117379.
- ^ Shen LW, Mao HJ, Wu YL, Tanaka Y, Zhang W (November 2017). "TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections". Biochimie. 142: 1–10. doi:10.1016/j.biochi.2017.07.016. PMC 7116903. PMID 28778717.
- ^ Depfenhart M, de Villiers D, Lemperle G, Meyer M, Di Somma S (August 2020). "Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy?". Internal and Emergency Medicine. 15 (5): 801–812. doi:10.1007/s11739-020-02383-3. PMC 7249615. PMID 32458206.
- ^ a b Mollica V, Rizzo A, Massari F (September 2020). "The pivotal role of TMPRSS2 in coronavirus disease 2019 and prostate cancer". Future Oncology. 16 (27): 2029–2033. doi:10.2217/fon-2020-0571. PMC 7359420. PMID 32658591.
- ^ a b Epstein RJ (2021). "The secret identities of TMPRSS2: Fertility factor, virus trafficker, inflammation moderator, prostate protector and tumor suppressor". Tumour Biology. 43 (1): 159–176. doi:10.3233/TUB-211502. PMID 34420994. S2CID 237268413.
- ^ Breining P, Frølund AL, Højen JF, Gunst JD, Staerke NB, Saedder E, Cases-Thomas M, Little P, Nielsen LP, Søgaard OS, Kjolby M (February 2021). "Camostat mesylate against SARS-CoV-2 and COVID-19-Rationale, dosing and safety". Basic & Clinical Pharmacology & Toxicology. 128 (2): 204–212. doi:10.1111/bcpt.13533. PMID 33176395.
- ^ "ACTG announces Camostat will not advance to phase 3 in outpatient treatment study for COVID-19". EurekAlert!. Retrieved 2021-07-01.
- ^ Shapira T, Monreal IA, Dion SP, Buchholz DW, Imbiakha B, Olmstead AD, et al. (March 2022). "A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic". Nature. 605 (7909): 340–348. Bibcode:2022Natur.605..340S. doi:10.1038/s41586-022-04661-w. PMC 9095466. PMID 35344983.
Further reading
[edit]- Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Lin B, Ferguson C, White JT, Wang S, Vessella R, True LD, et al. (September 1999). "Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2". Cancer Research. 59 (17): 4180–4184. PMID 10485450.
- Vaarala MH, Porvari KS, Kellokumpu S, Kyllönen AP, Vihko PT (January 2001). "Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues". The Journal of Pathology. 193 (1): 134–140. doi:10.1002/1096-9896(2000)9999:9999<::AID-PATH743>3.0.CO;2-T. PMID 11169526. S2CID 37552020.
- Afar DE, Vivanco I, Hubert RS, Kuo J, Chen E, Saffran DC, et al. (February 2001). "Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia". Cancer Research. 61 (4): 1686–1692. PMID 11245484.
- Jacquinet E, Rao NV, Rao GV, Zhengming W, Albertine KH, Hoidal JR (May 2001). "Cloning and characterization of the cDNA and gene for human epitheliasin". European Journal of Biochemistry. 268 (9): 2687–2699. doi:10.1046/j.1432-1327.2001.02165.x. PMID 11322890.
- Teng DH, Chen Y, Lian L, Ha PC, Tavtigian SV, Wong AK (June 2001). "Mutation analyses of 268 candidate genes in human tumor cell lines". Genomics. 74 (3): 352–364. doi:10.1006/geno.2001.6551. PMID 11414763.
- Wilson S, Greer B, Hooper J, Zijlstra A, Walker B, Quigley J, Hawthorne S (June 2005). "The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells". The Biochemical Journal. 388 (Pt 3): 967–972. doi:10.1042/BJ20041066. PMC 1183478. PMID 15537383.
- Soller MJ, Isaksson M, Elfving P, Soller W, Lundgren R, Panagopoulos I (July 2006). "Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer". Genes, Chromosomes & Cancer. 45 (7): 717–719. doi:10.1002/gcc.20329. PMID 16575875. S2CID 86518137.
- Tomlins SA, Mehra R, Rhodes DR, Smith LR, Roulston D, Helgeson BE, et al. (April 2006). "TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer". Cancer Research. 66 (7): 3396–3400. doi:10.1158/0008-5472.CAN-06-0168. PMID 16585160.
- Yoshimoto M, Joshua AM, Chilton-Macneill S, Bayani J, Selvarajah S, Evans AJ, et al. (June 2006). "Three-color FISH analysis of TMPRSS2/ERG fusions in prostate cancer indicates that genomic microdeletion of chromosome 21 is associated with rearrangement". Neoplasia. 8 (6): 465–469. doi:10.1593/neo.06283. PMC 1601467. PMID 16820092.
- Böttcher E, Matrosovich T, Beyerle M, Klenk HD, Garten W, Matrosovich M (October 2006). "Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium". Journal of Virology. 80 (19): 9896–9898. doi:10.1128/JVI.01118-06. PMC 1617224. PMID 16973594.
- Cerveira N, Ribeiro FR, Peixoto A, Costa V, Henrique R, Jerónimo C, Teixeira MR (October 2006). "TMPRSS2-ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions". Neoplasia. 8 (10): 826–832. doi:10.1593/neo.06427. PMC 1715930. PMID 17032499.
- Yoo NJ, Lee JW, Lee SH (March 2007). "Absence of fusion of TMPRSS2 and ETS transcription factor genes in gastric and colorectal carcinomas". APMIS. 115 (3): 252–253. doi:10.1111/j.1600-0463.2007.apm_652.x. PMID 17367471. S2CID 34487156.
- Winnes M, Lissbrant E, Damber JE, Stenman G (May 2007). "Molecular genetic analyses of the TMPRSS2-ERG and TMPRSS2-ETV1 gene fusions in 50 cases of prostate cancer". Oncology Reports. 17 (5): 1033–1036. doi:10.3892/or.17.5.1033. PMID 17390040.
- Tu JJ, Rohan S, Kao J, Kitabayashi N, Mathew S, Chen YT (September 2007). "Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: frequency and transcript variant analysis by RT-PCR and FISH on paraffin-embedded tissues". Modern Pathology. 20 (9): 921–928. doi:10.1038/modpathol.3800903. PMID 17632455.