TMPRSS2

Function

This 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 was demonstrated to be 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. The biological function of this gene is unknown.[6]

ERG 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.[7]

Relation to coronaviruses

Some coronaviruses, e.g. both SARS-CoV-1 and SARS-CoV-2 are activated by TMPRSS2 and can thus be inhibited by TMPRSS2 inhibitors.[8][9] "SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming.[10] A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option."[9] One 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 OTC (in most countries) mucolytic cough medicine bromhexine,[11] which is also being investigated as a possible treatment for COVID-19 itself as well.[12]

References
  1. GRCh38: Ensembl release 89: ENSG00000184012 - Ensembl, May 2017
  2. 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): 309–20. doi:10.1006/geno.1997.4845. PMID 9325052.
  6. "Entrez Gene: TMPRSS2 transmembrane protease, serine 2".
  7. 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): 443–54. doi:10.1016/j.ccr.2010.03.018. PMC 2874722. PMID 20478527.
  8. Huggins, DJ (November 2020). "Structural analysis of experimental drugs binding to the SARS-CoV-2 target TMPRSS2". Journal of Molecular Graphics and Modelling. 100. doi:10.1016/j.jmgm.2020.107710. PMC 7417922.
  9. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. (March 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 – Deutsches Primatenzentrum GmbH.
  10. 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.
  11. Shen, Li Wen; Mao, Hui Juan; Wu, Yan Ling; Tanaka, Yoshimasa; Zhang, Wen (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.
  12. Depfenhart, Markus; de Villiers, Danielle; Lemperle, Gottfried; Meyer, Markus; Di Somma, Salvatore (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.

Further reading
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