TMPRSS2

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. TMPRSS2 participates in proteolytic cascades necessary for normal physiological function of the prostate. Gene knockout mice lacking TMPRSS2 show no abnormalities.{{cite journal | vauthors = Sarker J, Das P, Sarker S, Roy AK, Momen AZ | title = A Review on Expression, Pathological Roles, and Inhibition of TMPRSS2, the Serine Protease Responsible for SARS-CoV-2 Spike Protein Activation | journal = Scientifica | volume = 2021 | pages = 2706789 | date = 2021 | pmid = 34336361 | pmc = 8313365 | doi = 10.1155/2021/2706789 | doi-access = free }}

File:His296,_Asp345,_and_Ser441_catalytic_triad.png, the histidine (cyan) acts as a general base to reset the serine and the aspartate (magenta) neutralizes the histidine in transition states during reactions that cause proteolytic cleavage. This structure was solved via X-ray crystallography with a resolution of 1.95 Angstroms (PDB: 7MEQ).{{cite journal | vauthors = Fraser BJ, Beldar S, Seitova A, Hutchinson A, Mannar D, Li Y, Kwon D, Tan R, Wilson RP, Leopold K, Subramaniam S, Halabelian L, Arrowsmith CH, Bénard F | display-authors = 6 | title = Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation | journal = Nature Chemical Biology | volume = 18 | issue = 9 | pages = 963–971 | date = September 2022 | pmid = 35676539 | doi = 10.1038/s41589-022-01059-7 | doi-access = free }} Image made in Chimera.{{Cite web |title=Supplemental Information 4: UCSF Chimera |doi=10.7717/peerj.4593/supp-4 |doi-access=free }}]]

File:TMPRSS2-_Solved_Structure.png side towards the top and the cytoplasmic side towards the bottom. Bound calcium ions are shown in blue and function as stabilizing cofactors. This view (generated in Chimera) illustrates the largely open conformation that exposes the catalytic triad.]]

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.{{cite journal | vauthors = Wettstein L, Kirchhoff F, Münch J | title = The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment | journal = International Journal of Molecular Sciences | volume = 23 | issue = 3 | pages = 1351 | date = January 2022 | pmid = 35163273 | pmc = 8836196 | doi = 10.3390/ijms23031351 | doi-access = free }} This serine protease activity is orchestrated by a catalytic triad containing the residues His296, Asp345, and Ser441. 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. A notable domain in the stem region that has been examined through mutational analysis is the low density lipoprotein receptor class A domain (LDLRA). 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). This domain may be implicated in the binding of extracellular molecules and other nearby cells.{{cite journal | vauthors = Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE | title = Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3 | journal = Genomics | volume = 44 | issue = 3 | pages = 309–320 | date = September 1997 | pmid = 9325052 | doi = 10.1006/geno.1997.4845 }}{{cite journal | vauthors = Wettstein L, Kirchhoff F, Münch J | title = The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment | journal = International Journal of Molecular Sciences | volume = 23 | issue = 3 | pages = 1351 | date = January 2022 | pmid = 35163273 | pmc = 8836196 | doi = 10.3390/ijms23031351 | doi-access = free }} 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.{{cite journal | vauthors = Guipponi M, Antonarakis SE, Scott HS | title = TMPRSS3, a type II transmembrane serine protease mutated in non-syndromic autosomal recessive deafness | journal = Frontiers in Bioscience | volume = 13 | issue = 13 | pages = 1557–1567 | date = January 2008 | pmid = 17981648 | doi = 10.2741/2780 | doi-access = free }}{{cite journal | vauthors = Afar DE, Vivanco I, Hubert RS, Kuo J, Chen E, Saffran DC, Raitano AB, Jakobovits A | display-authors = 6 | title = Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia | journal = Cancer Research | volume = 61 | issue = 4 | pages = 1686–1692 | date = February 2001 | pmid = 11245484 | url = https://pubmed.ncbi.nlm.nih.gov/11245484 }}

{{See also|ERG (gene)#TMPRSS2 gene fusion}}

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.{{cite journal | vauthors = Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, Wang X, Wu L, Li J, Hu M, Gong Y, Cheng H, Laxman B, Vellaichamy A, Shankar S, Li Y, Dhanasekaran SM, Morey R, Barrette T, Lonigro RJ, Tomlins SA, Varambally S, Qin ZS, Chinnaiyan AM | display-authors = 6 | title = An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression | journal = Cancer Cell | volume = 17 | issue = 5 | pages = 443–454 | date = May 2010 | pmid = 20478527 | pmc = 2874722 | doi = 10.1016/j.ccr.2010.03.018 }}

Some coronaviruses, e.g. SARS-CoV-1, MERS-CoV, and SARS-CoV-2 (although less well by the omicron variant{{cite journal | vauthors = Meng B, Abdullahi A, Ferreira IA, Goonawardane N, Saito A, Kimura I, Yamasoba D, Gerber PP, Fatihi S, Rathore S, Zepeda SK, Papa G, Kemp SA, Ikeda T, Toyoda M, Tan TS, Kuramochi J, Mitsunaga S, Ueno T, Shirakawa K, Takaori-Kondo A, Brevini T, Mallery DL, Charles OJ, Bowen JE, Joshi A, Walls AC, Jackson L, Martin D, Smith KG, Bradley J, Briggs JA, Choi J, Madissoon E, Meyer KB, Mlcochova P, Ceron-Gutierrez L, Doffinger R, Teichmann SA, Fisher AJ, Pizzuto MS, de Marco A, Corti D, Hosmillo M, Lee JH, James LC, Thukral L, Veesler D, Sigal A, Sampaziotis F, Goodfellow IG, Matheson NJ, Sato K, Gupta RK | display-authors = 6 | title = Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity | journal = Nature | volume = 603 | issue = 7902 | pages = 706–714 | date = March 2022 | pmid = 35104837 | pmc = 8942856 | doi = 10.1038/s41586-022-04474-x | bibcode = 2022Natur.603..706M }}), are activated by TMPRSS2 and can thus be inhibited by TMPRSS2 inhibitors.{{cite journal | vauthors = Huggins DJ | title = Structural analysis of experimental drugs binding to the SARS-CoV-2 target TMPRSS2 | journal = Journal of Molecular Graphics & Modelling | volume = 100 | pages = 107710 | date = November 2020 | pmid = 32829149 | pmc = 7417922 | doi = 10.1016/j.jmgm.2020.107710 }} SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming.{{cite journal | vauthors = Rahman N, Basharat Z, Yousuf M, Castaldo G, Rastrelli L, Khan H | title = Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2) | journal = Molecules | volume = 25 | issue = 10 | pages = 2271 | date = May 2020 | pmid = 32408547 | pmc = 7287752 | doi = 10.3390/molecules25102271 | doi-access = free }}

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.{{cite journal | vauthors = Jackson CB, Farzan M, Chen B, Choe H | title = Mechanisms of SARS-CoV-2 entry into cells | journal = Nature Reviews. Molecular Cell Biology | volume = 23 | issue = 1 | pages = 3–20 | date = January 2022 | pmid = 34611326 | pmc = 8491763 | doi = 10.1038/s41580-021-00418-x }} 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.

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.{{cite journal | vauthors = Zipeto D, Palmeira JD, Argañaraz GA, Argañaraz ER | title = ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19 | journal = Frontiers in Immunology | volume = 11 | pages = 576745 | date = 2020 | pmid = 33117379 | pmc = 7575774 | doi = 10.3389/fimmu.2020.576745 | doi-access = free }} By not releasing soluble ACE2, TMPRSS2 cleavage is more harmful.

A TMPRSS2 inhibitor such as camostat approved for clinical use blocked entry and might constitute a treatment option.{{cite journal | vauthors = Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S | display-authors = 6 | title = SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor | journal = Cell | volume = 181 | issue = 2 | pages = 271–280.e8 | date = April 2020 | pmid = 32142651 | pmc = 7102627 | doi = 10.1016/j.cell.2020.02.052 | doi-access = free }}

• {{lay source |template = cite press release|url = https://www.dpz.eu/en/home/single-view/news/die-vermehrung-von-sars-coronavirus-2-im-menschen-verhindern.html|title = Preventing spread of SARS coronavirus-2 in humans|date= March 5, 2020 |website = German Primate Center}} 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,{{cite journal | vauthors = Shen LW, Mao HJ, Wu YL, Tanaka Y, Zhang W | title = TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections | journal = Biochimie | volume = 142 | pages = 1–10 | date = November 2017 | pmid = 28778717 | pmc = 7116903 | doi = 10.1016/j.biochi.2017.07.016 }} which is also being investigated as a possible treatment for COVID-19 itself as well.{{cite journal | vauthors = Depfenhart M, de Villiers D, Lemperle G, Meyer M, Di Somma S | title = Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy? | journal = Internal and Emergency Medicine | volume = 15 | issue = 5 | pages = 801–812 | date = August 2020 | pmid = 32458206 | pmc = 7249615 | doi = 10.1007/s11739-020-02383-3 }} The fact that TMPRSS2 has no known irreplaceable function makes it a promising target for preventing SARS-CoV-2 virus transmission.

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.{{cite journal | vauthors = Mollica V, Rizzo A, Massari F | title = The pivotal role of TMPRSS2 in coronavirus disease 2019 and prostate cancer | journal = Future Oncology | volume = 16 | issue = 27 | pages = 2029–2033 | date = September 2020 | pmid = 32658591 | pmc = 7359420 | doi = 10.2217/fon-2020-0571 }}{{cite journal | vauthors = Epstein RJ | title = The secret identities of TMPRSS2: Fertility factor, virus trafficker, inflammation moderator, prostate protector and tumor suppressor | journal = Tumour Biology | volume = 43 | issue = 1 | pages = 159–176 | date = 2021 | pmid = 34420994 | doi = 10.3233/TUB-211502 | s2cid = 237268413 | doi-access = free }} Prostate cancer patients receiving androgen deprivation therapy have a lower risk of SARS-CoV-2 infection than those not receiving that therapy.

Camostat is an inhibitor of the serine protease activity of TMPRSS2. It is used to treat pancreatitis and reflux esophagitis.{{cite journal |vauthors=Breining P, Frølund AL, Højen JF, Gunst JD, Staerke NB, Saedder E, Cases-Thomas M, Little P, Nielsen LP, Søgaard OS, Kjolby M |title=Camostat mesylate against SARS-CoV-2 and COVID-19-Rationale, dosing and safety |journal=Basic & Clinical Pharmacology & Toxicology |volume=128 |issue=2 |pages=204–212 |date=February 2021 |pmid=33176395 |doi=10.1111/bcpt.13533|doi-access=free }} It was found not to be effective against COVID-19.{{Cite web|title=ACTG announces Camostat will not advance to phase 3 in outpatient treatment study for COVID-19|url=https://www.eurekalert.org/pub_releases/2021-06/actg-aac062421.php|access-date=2021-07-01|website=EurekAlert!|language=en}} A novel inhibitor of TMPRSS2 (N-0385) has been found to be effective against SARS-CoV-2 infection in cell and animal models.{{cite journal | vauthors = Shapira T, Monreal IA, Dion SP, Buchholz DW, Imbiakha B, Olmstead AD, Jager M, Désilets A, Gao G, Martins M, Vandal T, Thompson CA, Chin A, Rees WD, Steiner T, Nabi IR, Marsault E, Sahler J, Diel DG, Van de Walle GR, August A, Whittaker GR, Boudreault PL, Leduc R, Aguilar HC, Jean F | display-authors = 6 | title = A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic | journal = Nature | pages = 340–348 | date = March 2022 | volume = 605 | issue = 7909 | pmid = 35344983 | doi = 10.1038/s41586-022-04661-w | pmc = 9095466 | bibcode = 2022Natur.605..340S }}{{cite journal |vauthors=Pérez-Vargas J, Lemieux G, Thompson CA, Désilets A, Ennis S, Gao G, Gordon DG, Schulz AL, Niikura M, Nabi IR, Krajden M, Boudreault PL, Leduc R, Jean F |title=Nanomolar anti-SARS-CoV-2 Omicron activity of the host-directed TMPRSS2 inhibitor N-0385 and synergistic action with direct-acting antivirals |journal=Antiviral Research |volume=225 |issue= |pages=105869 |date=May 2024 |pmid=38548023 |doi=10.1016/j.antiviral.2024.105869|doi-access=free }}

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