With the COVID-19 spreads around the world, scientists have work hard to explore the mechanism of SARS-CoV-2 invasion. And there are many SARS-CoV-2-Host interactome targets which have been reported, such as ACE2, TMPRSS2 and CD147. The relationship between SARS-CoV-2 and TMPRSS2 was firstly reported in the study entitled “The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor 1 ACE2 and the cellular protease TMPRSS2 for entry into target cells” . Then, more and more studies about TMPRSS2 have been published. So what is the TMPRSS2? And how does SARS-CoV-2 invade human body via TMPRSS2?
1. What is The TMPRSS2?
Transmembrane protease serine 2, also known as TMPRSS2, is a member of transmembrane protease serines (TMPRSSs), which are a family of proteins with conserved serine protease domains located on the cell membrane. The basic structure of TMPRSSs is similar. The C-terminal protease domain is outside the cell, the N-terminal is located inside the cell, and it also has a single transmembrane domain. The difference lies in the backbone region.
As the Figure 1 shows, TMPRSS2 gene is located on human chromosome 21: 41, 464, 551-41, 531, 116. A significant feature of the TMPRSS2 gene is that several androgen receptor elements (AREs) are located upstream of the transcription start site and the first intron  .
Figure 1. A schematic diagram of TMPRSS2 genomic location
*This diagram is derived from the publication published on Biochimie 
The TMPRSS2 protein, encoded by TMPRSS2 gene, consists of 492 amino acids which anchors to the plasma membrane. As the Figure 2 shows, it converts to its form through autocatalytic cleavage between Arg255 and Ile256. After cleavage, the mature proteases are mostly membrane-bound, yet a noticeable portion of them can be liberated into the extracellular milieu. The protease catalytic domain contains a catalytic triad consisting of the amino acid residues His296, Asp345 and Ser441, corresponding to His57, Asp102 and Ser195 of chymotrypsinogen .
Figure 2. The location and structure of TMPRSS2 protein
*This diagram is derived from the publication published on Biochimie 
2. What is The Distribution of TMPRSS2?
The expression of TMPRSS2 has obvious tissue specificity. Human TMPRSS2 is an androgen-regulated, type II transmembrane-bound serine protease that is predominantly expressed in prostate, with relatively lower level of expression in lungs, colon, liver, kidneys and pancreas. According to in situ hybridization analysis of mouse embryos and adult tissues, mouse TMPRSS2 is also expressed in gastrointestinal tract, urogenital tract and respiratory tract epithelial cells, indicating that the expression distribution of TMPRSS2 in mice and humans is very similar. The tissue specific expression also suggests that diseases caused by abnormal TMPRSS2 may prefer to men than women.
3. What is The Function of TMPRSS2?
TMPRSS2 is closely related to prostate cancer. In 2005, most prostate cancers (up to 70%) were found to have fusion of the TMPRSS2 and oestrogen-regulated gene (ERG), both on chromosome 21. Soon thereafter, other members of erythroblast transformation-specific (ETS) variant gene (ETV) family were found to have gene fusions, although at much lower frequencies, including ETV1 (chromosome 7), ETV4 (chromosome 17), ETV5 (chromosome 3), and ETS domain-containing protein gene (ELK4, chromosome 1).
Taking the TMPRSS2 and ERG fusion as an example, gene fusion, also called gene rearrangement, often causes abnormal activation of certain genes. As the Figure 3 shows, the gene rearrangement consists of actual loss of genetic material between two genes on the same chromosome; note the deletion of intervening genes between TMPRSS2 and ERG on chromosome 21. A second form of fusion is due to translocation, when a gene moves to another location on the same chromosome or a different chromosome. Both mechanisms apply for the gene rearrangements in prostate cancer. Given the high prevalence of prostate cancer, this fusion gene is probably the most common fusion gene in human cancer. Further, TMPRSS2-ERG can be used as a diagnostic marker for prostate cancer.
Figure 2. Mechanism of TMPRESS2-ERG fusion (chromosome 21)
*This diagram is derived from the publication published on BJU Int. 
Additionally, besides its role in prostate cancer, it also related to virus. We will illustrate this function in the next section.
4. How is TMPRSS2 Related to Viruses?
In 2019, the study from Naoko Iwata-Yoshikawa et al. showed that TMPRSS2 activates the spike protein of highly pathogenic human coronavirus, such as severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV). In vitro, the activation of TMPRSS2 induces virus-cell membrane fusion at the cell surface. In this study, they examined the role of TMPRSS2 using animal models of SARS-CoV and MERS-CoV infection. The results showed that lack of TMPRSS2 in the airways reduces the severity of lung pathology after infection by SARS-CoV and MERS-CoV .
Actually, as early as 2011, Ilona Glowacka and others from the Hannover Medical School in German assessed whether the S (Spike glycoprotein) of SARS-CoV is proteolytically processed by TMPRSS2. In this study, the results of western blot analysis revealed that SARS S was cleaved into several fragments upon coexpression of TMPRSS2 (cis-cleavage) and upon contact between SARS S-expressing cells and TMPRSS2-positive cells (trans-cleavage). cis-cleavage resulted in release of SARS S fragments into the cellular supernatant and in inhibiting antibody-mediated neutralization. trans-cleavage activated SARS S on effector cells to fuse with target cells. It shows that TMPRSS2 may promote viral spread and pathogenesis by reducing viral recognition by neutralizing antibodies and by activating SARS S for cell-cell and virus-cell fusion .
5. How does SARS-CoV-2 Invade Human Body via TMPRSS2?
As you know, SARS-CoV-2 and the SARS-CoV share central biological properties and similar structure. Both SARS-CoV-2 and SARS-CoV belong to coronaviruses. Markus Hoffmann et al. suggest that coronaviruses use their spike proteins to select and enter target cells and insights into SARS-CoV-2 spike (S)-driven entry might facilitate assessment of pandemic potential and reveal therapeutic targets. In their study, they demonstrated that SARS-CoV-2-S uses the SARS-CoV receptor, ACE2, for entry and the cellular protease TMPRSS2 for SARS-CoV-2-S priming. A TMPRSS2 inhibitor blocked entry and might constitute a treatment option. These results revealed important commonalities between SARS-CoV-2 and SARS-CoV infection, which might translate into similar transmissibility and disease pathogenesis.
In fact, research suggests that there are two ways for coronavirus to enter cells. One is that the cell surface is mediated by TMPRSS2, and the other is mediated by cathepsin L in the nucleus. Stefanie Gierer et al. found that TMPRSS2 and cathepsins B and L can activate the novel human coronavirus EMC (hCoV-EMC) and fuse with target cells. Therefore, TMPRSS2 and cathepsin have become potential targets for controlling hCoV-EMC  .
In the research of influenza virus, a considerable number of researchers have found that TMPRSS2 can increase the susceptibility of the host. For example, TMPRSS2 plays an important role in the proteolytic activation of hemagglutinin (HA) protein of influenza A virus (IAV), and TMPRSS2 promotes The replication of H7N9 and seasonal influenza viruses in the body is a key factor in the respiratory infection of mice caused by H7N9 and H1N1 viruses .
In 2014, Adeline Heurich and others once again proved the role of TMPRSS2 and HAT in coronavirus. They found that these two enzymes can cleave and activate the spike protein of SARS-CoV for membrane fusion. In addition, these enzymes also cleave SARS-CoV receptor ACE2. It is mentioned in the literature that the arginine and lysine residues in the amino acid sequence 697-716 of ACE2 are essential for the cleavage of TMPRSS2 and HAT .
6. The Latest Progression of TMPRSS2 Research
In this section, we collect several latest progression of TMPRSS2 research as follows:
- On March 5, 2020, Stefan Pöhlmann and Markus Hoffmann from the University of Göttingen in Germany published a study on the Cell entitled "SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor". They demonstrated that SARS-CoV-2 uses the SARS-CoV receptor ACE2 to enter the cell, and the serine protease TMPRSS2 is used to activate the S (Spike glycoprotein). A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. The results of this study revealed important commonalities between SARS-CoV-2 and SARS-CoV infection and identified a potential target for antiviral intervention .
- On April 22, 2020, a study was pre-published on the Cell entitled "SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and detected in specific cell subsets across tissues". In this study, researchers leveraged human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. They identified ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. The results of this study suggested that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection .
- n May 6, 2020, the team of Professor Li Fang from the University of Minnesota published a paper entitled "Cell entry mechanisms of SARS-CoV-2" on the Proceedings of the National Academy of Sciences of the United States of America (PNAS). Using biochemical and pseudovirus entry assays and SARS-CoV as a comparison, they identified key cell entry mechanisms of SARS-CoV-2 that potentially contribute to the immune evasion, cell infectivity, and wide spread of the virus. Moreover, this study also clarified conflicting reports from recent studies on cell entry of SARS-CoV-2. Finally, by highlighting the potency and the evasiveness of SARS-CoV-2, the study provides insight into intervention strategies that target its cell entry mechanism .
- On May 9, 2020, the team of Elia J Duh from Johns Hopkins University published an article entitled "ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection" on bioRxiv. The results of this study indicate that ocular surface cells including conjunctiva are susceptible to infection by SARS-CoV-2, and could therefore serve as a portal of entry as well as a reservoir for person-to-person transmission of this virus. This highlights the importance of safety practices including face masks and ocular contact precautions in preventing the spread of COVID-19 disease .
- n May 13, 2020, the team of Professor Kwok Yung Yuen from Medicine of the University of Hong Kong published an article entitled" Infection of bat and human intestinal organoids by SARS-CoV-2" on Nature Medicine, It was confirmed that SARS-CoV-2 can infect the intestinal organs of humans and bats, indicating that SARS-CoV-2 may be transmitted through the intestine of the host. The researchers also found that in the differentiated human intestinal organs, the expression of ACE2 and TMPRSS2 required for SARS-CoV-2 to invade host cells were significantly increased .
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 Lingli Zhou, Zhenhua Xu, et al. ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection [J]. bioRxiv. 2020.
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