TMPRSS2

from Wikipedia, the free encyclopedia
Transmembrane serine protease 2
other names
  • Epitheliasin
  • Serine protease 10
Properties of human protein
Mass / length primary structure 492 amino acids
Isoforms 2
Identifier
Gene names TMPRSS2  ; PRSS10; PP9284
External IDs
Enzyme classification
EC, category 3.4.21. ,  Hydrolase
MEROPS S01.247
Response type hydrolysis
Occurrence
Parent taxon Eukaryotes
Orthologue
human House mouse
Entrez 7113 50528
Ensemble ENSG00000184012 ENSMUSG00000000385
UniProt O15393 Q9JIQ8
Refseq (mRNA) NM_001135099 NM_015775
Refseq (protein) NP_001128571 NP_056590
Gene locus Chr 21: 41.46 - 41.53 Mb Chr 16: 97.56 - 97.61 Mb
PubMed search 7113 50528

The transmembrane serine protease 2 (English: t rans m embrane pr otease s erine s ubtype 2 , TMPRSS2 ) is an enzyme that in humans by the TMPRSS2 - gene is encoded. It is one of 14 identified members (as of 2017) of the family of type II transmembrane serine proteases .

construction

The TMPRSS2 gene encodes a protein that belongs to the serine protease family. The encoded protein contains several protein domains :

function

Serine proteases are involved in many physiological and pathological processes. It has been shown that the TMPRSS2 gene is upregulated by androgenic hormones in prostate cancer cells and downregulated in prostate cancer tissue that is independent of androgenic hormones.

The TMPRSS2 gene is located on chromosome 21 in humans, but it is currently unknown what physiological role TMPRSS2 plays in trisomy 21 , which is a chromosomal aberration .

The role of TMPRSS2 in virion entry into cells

The enzymes trypsin , furin and other proprotein convertases, cathepsins , transmembrane serine proteases (TMPRSS) and elastases play a role in the cell entry of coronaviruses ( Coronaviridae ). The proteases TMPRSS2 and TMPRSS11a, which are increasingly present in the respiratory tract and are expressed on cell surfaces , promote the entry of SARS-CoV- 1 viruses. For the TMPRSS protease TMPRSS11d - also known as human airway trypsin-like protease (HAT) - a proteolytic activation of the S protein of SARS-CoV-1 has been demonstrated. TMPRSS2 in turn forms a complex with the ACE2 receptor , which enables the virus to penetrate efficiently directly on the cell surface. TMPRSS2 and TMPRSS11D activate the S protein by cleaving it into the S1 and S2 subunits, thus enabling endosome- independent cell entry at the cell membrane .

Virus-based therapies include monoclonal antibodies , antiviral peptides that dock onto the S protein of viruses, viral nucleic acid synthesis inhibitors, and inhibitors that dock onto other viral structures and accessory proteins. Camostat is a synthetic, low molecular weight serine protease inhibitor that is used to treat chronic pancreatitis with minimal side effects.

Aprotinin , a polypeptide purified from bovine lung consisting of 58 amino acid residues, inhibits serine proteases and suppresses the cleavage of hemagglutinin on the virus envelope of the influenza virus, thus stopping its reproduction. Camostat is a therapeutic agent for cancer , pancreatitis, and liver fibrosis . In the treatment of the human ciliated epithelium cells ( English human tracheal epithelial , HTE) with a camostat concentration of 10 mg / mL, the reduced influenza A virus H1N1 - titer in the supernatant of viral culture of the strain A / PR / 8 / 34 significant. Another study showed that Camostat leads to a ten-fold reduction in the SARS-CoV titer in Calu3 cells (human lung cancer cell line ). At a Camostat concentration of 10 μM, the cell entry of MERS-CoV into Vero cells is inhibited 14-fold. Three days after a MERS-CoV infection, the amount of viral RNA in the supernatant of the Calu3 cell culture is reduced by a factor of 270 at a Camostat concentration of 100 μM . The serine protease inhibitor nafamostat blocks MERS-CoV infection in vitro by suppressing TMPRSS2 activity and, at a concentration of 1 nM, leads to a 100-fold reduction in virus entry, which is more efficient than camostat. Bromhexine hydrochloride (a component of antitussives , also the prostate cancer - metastasis suppressed mice) could also as an inhibitor of TMPRSS2 for the treatment of influenza virus and coronavirus infections are used.

Other FDA- approved serine protease inhibitors such as 4- (2-aminoethyl) benzenesulfonyl fluoride hydrochloride and leupeptin have different antiviral activities. Ovomucoid , a trypsin inhibitor, at a concentration of 50 µM inhibits the spread of influenza A virus H1N1 (strain A / Memphis / 14/96) more efficiently than aprotinin. 3-Amidinophenylalanyl derivatives could inhibit TMPRSS2 with a concentration in the nanomolar range. It was also shown that three benzamidine derivatives as peptidomimetics inhibit the influenza A virus H1N1 infection of the strains A / Memphis / 14/96 and A / Hamburg / 5/2009 differently in TMPRSS2 and HAT-expressed cells.

In knockout mice in which the TMPRSS2 gene is deactivated, intranasal stimulation with polyinosinic acid: polycytidylic acid (an immune stimulant , abbreviated to poly I: C) showed a weakened chemokine and / or cytokine reaction in the immune system play a role. They also lost weight and the virus dynamics in the lungs decreased. Therefore, TMPRSS2 plays an important role in the viral spread of SARS-CoV and MERS-CoV within the airways of mouse models and in murine immunopathology .

SARS-CoV-2

A study carried out by Markus Hoffmann and Hannah Kleine-Weber from the German Primate Center together with other researchers confirms that the SARS-CoV-2 virus also confirms the presence of the ACE2 receptor and the TMPRSS2 enzyme in the cell membrane of lung cells needed, which cleaves the S protein on the virus envelope in order to be able to penetrate the lung cell. According to this study, the well-known inhibitor for TMPRSS2, Camostat, significantly reduces the probability of penetration of SARS-CoV-2 in cell experiments in vitro and could be suitable for treatment.

Individual evidence

  1. ↑ B. Knudsen, J. Lucas, P. Nelson: Serine Proteases (Type II) Spanning the Plasma Membrane. In: M. Schwab (Ed.): Encyclopedia of Cancer . Springer, Berlin, Heidelberg, 2011. doi : 10.1007 / 978-3-642-16483-5_5257
  2. ↑ a b Ariane Paoloni-Giacobino, Haiming Chen, Manuel C. Peitsch, Colette Rossier, Stylianos E. Antonarakis: Cloning of the TMPRSS2 genes, Which Encodes a Novel Serine Protease with Transmembrane, LDLRA, and SRCR domain sand maps to 21q22.3 . In: Genomics . tape 44 . Geneva, Switzerland 1997, p. 309-320 .
  3. ^ Jean Kaoru Millet, Gary R. Whittaker: Host cell proteases: critical determinants of coronavirus tropism and pathogenesis . In: Virus Res. April 16, 2015, doi : 10.1016 / j.virusres.2014.11.021 (English).
  4. ↑ a b c A. Shulla, T. Heald-Sargent, G. Subramanya, J. Zhao, S. Perlman, T. Gallagher: A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry. In: Journal of Virology . Volume 85, number 2, January 2011, pp. 873-882, doi : 10.1128 / JVI.02062-10 , PMID 21068237 , PMC 3020023 (free full text).
  5. ↑ Shirato K, Kanou K, Kawase M, Matsuyama S .: "Clinical Isolates of Human Coronavirus 229E Bypass the Endosome for Cell Entry." In: J Virol. Dec 2016, doi : 10.1128 / JVI.01387-16 , PMID 27733646 .
  6. ↑ A. Zumla, JF Chan, EI Azhar, DS Hui, KY Yuen: Coronaviruses - drug discovery and therapeutic options. In: Nature reviews. Drug discovery. Volume 15, number 5, 05 2016, pp. 327-347, doi : 10.1038 / nrd. 2015.37 , PMID 26868298 (review).
  7. ↑ JK Sai, M. Suyama, Y. Kubokawa, Y. Matsumura, K. Inami, S. Watanabe: Efficacy of camostat mesilate against dyspepsia associated with non-alcoholic mild pancreatic disease. In: Journal of gastroenterology. Volume 45, Number 3, March 2010, pp. 335-341, doi : 10.1007 / s00535-009-0148-1 , PMID 19876587 .
  8. ^ R. Talukdar, RK Tandon: Pancreatic stellate cells: new target in the treatment of chronic pancreatitis. In: Journal of gastroenterology and hepatology. Volume 23, Number 1, January 2008, pp. 34-41, doi : 10.1111 / j.1440-1746.2007.05206.x , PMID 17995943 (review).
  9. ↑ a b Chan JFW, Lau SKP, To KKW, Cheng VCC, Woo PCY, Yuen KY: Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease . In: Clin Microbiol Rev . March 15, 2015, doi : 10.1128 / CMR.00102-14 (English).
  10. ↑ AV Ovcharenko, O. P. Zhirnov: Aprotinin aerosol treatment of influenza and paramyxovirus bronchopneumonia of mice. In: Antiviral research. Volume 23, Number 2, February 1994, pp. 107-118, doi : 10.1016 / 0166-3542 (94) 90038-8 , PMID 7511880 .
  11. ^ A b M. Yamamoto, S. Matsuyama, X. Li, M. Takeda, Y. Kawaguchi, JI Inoue, Z. Matsuda: Identification of Nafamostat as a Potent Inhibitor of Middle East Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the Split-Protein-Based Cell-Cell Fusion Assay. In: Antimicrobial agents and chemotherapy. Volume 60, number 11, 11 2016, pp. 6532-6539, doi : 10.1128 / AAC.01043-16 , PMID 27550352 , PMC 5075056 (free full text).
  12. ↑ JM Lucas, C. Heinlein, T. Kim, SA Hernandez, MS Malik, LD True, C. Morrissey, E. Corey, B. Montgomery, E. Mostaghel, N. Clegg, I. Coleman, CM Brown, EL Schneider , C. Craik, JA Simon, A. Bedalov, PS Nelson: The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. In: Cancer discovery. Volume 4, number 11, November 2014, pp. 1310-1325, doi : 10.1158 / 2159-8290.CD-13-1010 , PMID 25122198 , PMC 4409786 (free full text).
  13. ↑ a b E. Böttcher, C. Freuer, T. Steinmetzer, HD Klenk, W. Garten: MDCK cells that express proteases TMPRSS2 and HAT provide a cell system to propagate influenza viruses in the absence of trypsin and to study cleavage of HA and its inhibition. In: Vaccine . Volume 27, number 45, October 2009, pp. 6324-6329, doi : 10.1016 / j.vaccine.2009.03.029 , PMID 19840668 .
  14. ↑ G. Simmons, S. Bertram, I. Glowacka, I. Steffen, C. Chaipan, J. Agudelo, K. Lu, AJ Rennekamp, ​​H. Hofmann, P. Bates, S. Pöhlmann: Different host cell proteases activate the SARS-coronavirus spike-protein for cell-cell and virus-cell fusion. In: Virology. Volume 413, number 2, May 2011, pp. 265-274, doi : 10.1016 / j.virol.2011.02.020 , PMID 21435673 , PMC 3086175 (free full text).
  15. ↑ D. Meyer, F. Sielaff, M. Hammami, E. Böttcher-Friebertshäuser, W. Garten, T. Steinmetzer: Identification of the first synthetic inhibitors of the type II transmembrane serine protease TMPRSS2 suitable for inhibition of influenza virus activation. In: The Biochemical journal. Volume 452, number 2, June 2013, pp. 331-343, doi : 10.1042 / BJ20130101 , PMID 23527573 .
  16. ^ E. Böttcher-Friebertshäuser, C. Freuer, F. Sielaff, S. Schmidt, M. Eickmann, J. Uhlendorff, T. Steinmetzer, HD Klenk, W. Garten: Cleavage of influenza virus hemagglutinin by airway proteases TMPRSS2 and HAT differs in subcellular localization and susceptibility to protease inhibitors. In: Journal of Virology . Volume 84, number 11, June 2010, pp. 5605-5614, doi : 10.1128 / JVI.00140-10 , PMID 20237084 , PMC 2876594 (free full text).
  17. ↑ Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N .: TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection . In: "J Virol" . March 5, 2019, doi : 10.1128 / JVI.01815-18 (English).
  18. ↑ Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder, Nadine Krüger, Tanja Herrler, Sandra Erichsen, Tobias S. Schiergens, Georg Herrler, Nai-Huei Wu, Andreas Nitsche, Marcel A. Müller, Christian Drosten, Stefan Pöhlmann: SARS- CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor . Cell (2020), doi : 10.1016 / j.cell.2020.02.052