TMPRSS2

Official Full Name

transmembrane serine protease 2

Organism

Homo sapiens

GeneID

7113

Background

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. This protein also facilitates entry of viruses into host cells by proteolytically cleaving and activating viral envelope glycoproteins. Viruses found to use this protein for cell entry include Influenza virus and the human coronaviruses HCoV-229E, MERS-CoV, SARS-CoV and SARS-CoV-2 (COVID-19 virus). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2020]

Synonyms

PRSS10;

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Detailed Information

The strategic localization of transmembrane protease serine 2 (TMPRSS2), a membrane-bound serine protease, has gained interest due to its highly localized expression in prostate cancer cells and its role in carcinogenesis. The TMPRSS2-encoded serine protease is expressed as a 70 kDa full-length form and a cleaved 32 kDa protease domain. The protease domain of this protein is considered to be cleaved and secreted into cell media after autocleavage. Researchers speculate the strategic localization of TMPRSS2 to the cancer cell surface may allow this unique serine protease to mediate signal transduction between the cancer cell and its extracellular environment, and to regulate different cellular responses.

TMPRSS2-erg gene fusion in prostate cancer

Gene fusions resulting from chromosomal rearrangements are known to play a crucial role in the initial steps of tumorigenesis. Tomlins et al. first described a gene fusion between TMPRSS2 gene and ETS (Erythroblastosis Virus E26 Transformation-Specific) family genes in prostate cancer, involving the 5´- untranslated region of TMPRSS2 and the encoding region of some transcription factors such as the ETS variant 1 gene (ETV1) or ETS-related gene (ERG). The ETS transcription factor family is one of the largest families of transcription regulators. ETS transcription factors play an important role in diverse biological processes, including cell proliferation, differentiation, apoptosis, angiogenesis and invasiveness. Important studies in recent years showed the significance of the TMPRSS2:ERG gene fusion in prostate cancer, and most of them suggested that the presence of the fusion gene product denotes an unfavorable outcome. The most direct result for the TMPRSS2:ERG gene fusion was the significant upregulation of the ERG gene, which is not normally expressed in prostate epithelia, and is probably to be involved in prostate cancer development by enhancing tumor angiogenesis. The TMPRSS2-ERG gene fusion accounts for most recurrent gene fusions in prostate cancer, with a frequency of 40-70%, which provides an idea of its potential as a biomarker. In addition, ERG gene silencing could significantly inhibit prostate cancer cell proliferation, and induce G0/G1 cell cycle arrest in prostate cancer cells. These results showed that not only the alteration of TMPRSS2 and ERG gene could be a specific marker in prostate cancer, but also could be a potential therapeutic target in prostate cancer.

TMPRSS2 and coronavirus

Pathogenic microorganisms have always been a major threat to human health. For other etiological agents including influenza virus and coronavirus, however, humans have not found an effective control method. In the 21st century alone, five large-scale respiratory virus epidemics or pandemics have occurred worldwide: the viruses responsible are SARS-CoV, 2009 H1N1 pandemic influenza A virus, MERS-CoV, Asian H7N9 influenza A virus and SARS-CoV-S2 in 2019. Recently, a great deal of evidence has indicated that TMPRSS2 plays a critical role in SARS, MERS coronavirus, 2013 Asian H7N9 influenza virus and several H1N1 subtype influenza A viruses infections, suggesting that targeting TMPRSS2 could be a novel antiviral strategy to treat coronavirus and some low pathogenic influenza virus infections.

TMPRSS2 Figure 1. The replication cycle of coronavirus and the proteolytic cleavage of the host proteases. (Shen L W, et al. 2017)

The SARS-CoV S protein can be cleaved by a wide variety of host proteases, such as TMPRSS2, MSPL, DESC1, HAT, Factor Xa and cathepsin L/B. It has been shown that SARS-CoV enters into cells through two distinct pathways: one is mediated by TMPRSS2 at the cell surface and the other done via cathepsin L/B in the endosome. The serine protease inhibitor camostat can effectively protect mice infected with the otherwise lethal SARS-CoV from death, but treatment with both serine and cathepsin inhibitors failed to improve survival significantly over that achieved with camostat alone, suggesting that SARS-CoV propagation and pathogenesis is mediated by TMPRSS2 rather than cathepsin in vivo. Kawase et al. found that SARS-CoV entry increased 2.6-fold in the presence of TMPRSS2; on the contrary, siRNA targeting TMPRSS2 caused a five-fold decrease in SARS-CoV entry into Calu-3 cells. Collectively, the obtained evidence indicates that TMPRSS2 plays an important role in SARS-CoV infection.

Recently, several studies indicate that SARS-CoV-2 (a novel coronavirus disease that emerged since December 2019 and spread rapidly worldwide) spread also relies on TMPRSS2 activity, although SARS-CoV-S2 infection of Calu-3 cells was inhibited but not abrogated by camostat mesylate, likely reflecting residual S protein priming by CatB/L. One can speculate that furin-mediated cleavage at the S1/S2 site in infected cells might promote subsequent TMPRSS2-dependent entry into target cells. Generally, TMPRSS2 as a host cell factor is vital for the spread of several clinically relevant viruses, including influenza A viruses and coronaviruses. In contrast, TMPRSS2 is dispensable for development and homeostasis and thus constitutes an attractive drug target. It is noteworthy that the serine protease inhibitor camostat mesylate, which blocks TMPRSS2 activity, has been approved in Japan for human use, although for an unrelated indication. Thus, this compound or related ones with potentially increased antiviral activity could be considered for off-label treatment of SARS-CoV-2 infected patients.

References:

Markus Hoffmann et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically-proven protease inhibitor. Cell, 2020
Shen L W, et al. TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections. Biochimie, 2017, 142: 1-10.
Burdova A, et al. TMPRSS2-ERG gene fusion in prostate cancer. Biomedical Papers of the Medical Faculty of Palacky University in Olomouc, 2014, 158(4).
Wang Z, et al. Significance of the TMPRSS2: ERG gene fusion in prostate cancer. Molecular medicine reports, 2017, 16(4): 5450-5458.
Lam D K, et al. TMPRSS2, a novel membrane-anchored mediator in cancer pain. Pain, 2015, 156(5): 923.

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