Since the outbreak of the novel coronavirus disease 2019 (COVID-19) from late 2019 to early 2020, as of December 27, 2021, this infectious disease has caused infections or deaths in over 280 million people worldwide. This epidemic is caused by the novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which primarily interacts with host factors in the human body during infection, such as angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), Furin, etc. TMPRSS2 is also implicated in certain cancers and COVID-19 infections. Therefore, summarizing TMPRSS2 distribution, structure, function, and mechanisms of action will deepen our understanding of TMPRSS2 and contribute to subsequent research on the pathogenicity of SARS-CoV-2, antiviral drugs, vaccines, and so forth.
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Fig 1. Structure and function of TMPRSS2 (Mantzourani C., et al. 2022).
Introduction of TMPRSS2
TMPRSS2 is widely present in various organisms, such as humans, chimpanzees, rhesus macaques, dogs, cattle, mice, chickens, zebrafish, Caenorhabditis elegans, and frogs. It is encoded by the TMPRSS2 gene, which is highly conserved and has two subtypes that can self-catalyze and activate. The TMPRSS2 gene is located at position 22 on the long arm of chromosome 21 and consists of 15 exons and an open reading frame of 492 amino acids. It contains androgen response elements in the 5' untranslated region (5'UTR), thus, the transcription of TMPRSS2 can be regulated by stimulating androgens such as testosterone and dihydrotestosterone.
The mRNA transcribed from the TMPRSS2 gene can express two subtypes through selective splicing. One subtype is subtype II composed of 492 amino acids, and the other subtype I has an extended cytoplasmic domain at the N-terminus (including an additional 37 amino acids). Both subtypes have the same transmembrane and extracellular domains. Subtype I has a longer N-terminus than subtype II, which gives subtype I a higher membrane localization and self-catalytic activation ability. Both subtypes can cleave and activate viral proteins, co-localize with viral hemagglutinins, such as cleaving the spike protein (S protein) of SARS-CoV and activating the S2 domain of the S protein, thereby facilitating the fusion of the virus with the target cell membrane without relying on tissue proteases.
Protein Structure
The protein structure of TMPRSS2 is mainly divided into three major regions: intracellular region, transmembrane region, and extracellular region. The intracellular region is at the N-terminus of the peptide chain, possibly cross-linking with the cytoskeleton and transmitting intracellular signaling molecules. The transmembrane region is a type II transmembrane structure domain that can connect the peptide catalytic domain and the cell membrane through disulfide bonds. The extracellular region mainly consists of the protease domain, including three parts: the first is the LDL receptor class A (LDLRA) domain responsible for binding calcium; the second is the scavenger receptor cysteine-rich (SRCR) domain involved in binding other cell surface or extracellular molecules; the third is the serine protease domain, which can cleave the S protein at arginine or lysine residues. The extracellular region of TMPRSS2 is crucial, mediating protein-protein interactions and cleaving cell membrane receptors, growth factors, cytokines, and extracellular substances.
Function of TMPRSS2
In physiological and pathological conditions, TMPRSS2 is associated with digestion, tissue remodeling, coagulation, reproduction, inflammatory response, tumor cell invasion, apoptosis, pain, etc. There are two key mechanisms of action of TMPRSS2: firstly, the TMPRSS2 gene can fuse with the erythroblast transformation-specific-related gene (ERG) to form a gene expressing an oncogenic transcription factor, which is the most common chromosomal aberration in prostate cancer (PCa); secondly, TMPRSS2 can cleave and activate various viral proteins involved in the fusion of viruses with target cells, such as promoting virus entry into target cells during SARS-CoV and SARS-CoV-2 infection by activating the S protein and cooperating with the ACE2 receptor. It can also cleave the surface glycoprotein hemagglutinin (HA) of H1N1 and H7N9 influenza viruses to facilitate the fusion of influenza viruses with target cell membranes, playing a mediating role in the invasion and spread of influenza.
TMPRSS2 and Human Diseases
TMPRSS2 in Cancer
TMPRSS2 plays a significant role in the occurrence, development, and progression of various cancers, exhibiting different functions in different cancer categories. In prostate cancer, TMPRSS2 is regulated by androgens and is highly expressed in both prostate secretory epithelium and cancer tissue. It promotes prostate cancer cell invasion, tumor growth, and metastasis by activating proteinase matriptase and degrading extracellular matrix proteins. TMPRSS2 can also fuse with ERG to form an oncogenic transcription factor, which is a common molecular feature in prostate cancer, suggesting its potential as a biomarker for prostate cancer prognosis. In lung cancer, the relationship with TMPRSS2 is complex. While some studies suggest TMPRSS2 may act as a tumor suppressor gene in lung adenocarcinoma and squamous cell carcinoma, further research is needed to elucidate the mechanisms. Moreover, TMPRSS2-ERG fusion genes found in prostate cancer patients with concurrent lung cancer may contribute to metastasis and worsen outcomes, implying potential diagnostic and therapeutic implications of TMPRSS2 in other malignancies. In colorectal cancer, TMPRSS2 is highly expressed in both normal and malignant tissues, with higher levels observed in cancerous tissues. Elevated TMPRSS2 expression, along with increased ACE2 levels, may make colorectal cancer patients more susceptible to microbial infections facilitated by TMPRSS2. Some studies suggest that colorectal cancer patients are more prone to SARS-CoV-2 infection and exhibit more complications, but further investigation is required to understand the relationship between TMPRSS2, colorectal cancer, and SARS-CoV-2.
TMPRSS2 in Virus Infections
TMPRSS2 plays a crucial role in virus infections, particularly with influenza and coronaviruses. In influenza viruses, TMPRSS2 acts as the primary activator in human respiratory cells for influenza A viruses and in type II pneumocytes for influenza B viruses, facilitating infection and inter-host transmission. TMPRSS2 cleaves the surface glycoprotein hemagglutinin (HA) of influenza viruses, promoting the fusion of viral and endosomal membranes, thereby facilitating viral entry into host cells. TMPRSS2 is involved in the invasion of host cells by various influenza virus subtypes, and high expression or mutations of TMPRSS2 increase the risk of severe influenza infections. Broad-spectrum protease inhibitors can inhibit influenza virus transmission, suggesting TMPRSS2 inhibitors as potential antiviral drugs.
In coronaviruses, TMPRSS2 facilitates the uptake of certain coronaviruses by target cells and plays a crucial role in viral infection. TMPRSS2 cleaves the spike protein (S protein) of coronaviruses, promoting viral entry into target cells. TMPRSS2 cleaves S protein at two sites, enhancing virus-cell fusion. Additionally, TMPRSS2 can induce target cell uptake of viruses when co-expressed with ACE2, suggesting its potential role in promoting virus entry. Furthermore, TMPRSS2 plays a crucial role in the pancreatic protease-independent and multi-cycle infection of group A rotaviruses, the leading cause of human and animal diarrheal diseases worldwide. TMPRSS2 activates the cleavage of rotavirus surface proteins VP7 and VP4, promoting virus maturation and infectivity. TMPRSS2 gene expression induces similar or higher levels of rotavirus growth in culture, aiding in rotavirus-related research and development. Despite these findings, the exact mechanisms of rotavirus infection in vivo remain to be elucidated.
Conclusion
TMPRSS2 plays a significant role in both tumor development and viral infections. However, the specific mechanisms of TMPRSS2, including its involvement in host signaling pathways and immune responses, require further investigation. Additionally, it remains to be explored whether TMPRSS2 has other biological functions and participates in other types of tumor and viral infection processes. Given its involvement in certain tumors and viral infections, and its impact on virus infections in tumor initiation, TMPRSS2 could serve as a drug target for the development of novel anticancer and antiviral medications. This approach could offer new avenues for drug development and disease prevention and treatment.
References
- Mantzourani C., et al. The discovery and development of transmembrane serine protease 2 (TMPRSS2) inhibitors as candidate drugs for the treatment of COVID-19. Expert Opinion on Drug Discovery. 2022, 17(3): 231-46.
- dos Santos Nascimento I.J., et al. Molecular modeling targeting Transmembrane Serine Protease 2 (TMPRSS2) as an alternative drug target against coronaviruses. Current Drug Targets. 2022, 23(3): 240-59.
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