TMPRSS2

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
TMPRSS2
Identifiers
AliasesTMPRSS2, PP9284, PRSS10, transmembrane protease, serine 2, transmembrane serine protease 2
External IDsOMIM: 602060 MGI: 1354381 HomoloGene: 4136 GeneCards: TMPRSS2
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001135099
NM_005656
NM_001382720

NM_015775

RefSeq (protein)

NP_001128571
NP_005647
NP_001369649

NP_056590

Location (UCSC)Chr 21: 41.46 – 41.53 MbChr 16: 97.37 – 97.41 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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 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]

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.[10]

Coronaviruses[edit]

Some coronaviruses, e.g. SARS-CoV-1, MERS-CoV, and SARS-CoV-2 (before the omicron variant), are activated by TMPRSS2 and can thus be inhibited by TMPRSS2 inhibitors.[11][12] SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming.[13]

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.[14] 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.[14]

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.[15] By not releasing soluble ACE2, TMPRSS2 cleavage is more harmful.[15]

A TMPRSS2 inhibitor such as camostat approved for clinical use blocked entry and might constitute a treatment option.[12][14] 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 overt-the-counter (in most countries) mucolytic cough medicine bromhexine,[16] which is also being investigated as a possible treatment for COVID-19 itself as well.[17] 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.[18][19] Prostate cancer patients receiving androgen deprivation therapy have a lower risk of SARS-CoV-2 infection than those not receiving that therapy.[18][19]

Inhibitors[edit]

Camostat is an inhibitor of the serine protease activity of TMPRSS2. It is used to treat pancreatitis and reflux esophagitis. It was found not to be effective against COVID-19. A novel inhibitor of TMPRSS2 has been found to be effective against SARS-CoV-2 infection in cell and animal models.[20]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000184012 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000385 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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.
  6. ^ a b "Entrez Gene: TMPRSS2 transmembrane protease, serine 2".
  7. ^ a b "UniProt Protein: TMPS2_HUMAN transmembrane protease".
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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.
  19. ^ 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.
  20. ^ 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. doi:10.1038/s41586-022-04661-w. PMC 9095466. PMID 35344983.

Further reading[edit]