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      Gene of the month: TMPRSS2 (transmembrane serine protease 2)

      research-article
      ,
      Journal of Clinical Pathology
      BMJ Publishing Group
      genetics, prostate, carcinoma, virology, enzymes

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          Abstract

          Transmembrane serine protease 2 is encoded by the TMPRSS2 gene. The gene is widely conserved and has two isoforms, both being autocatalytically activated from the inactive zymogen form. A fusion gene between the TMPRSS2 gene and ERG (erythroblast-specific-related gene), an oncogenic transcription factor, is the most common chromosomal aberration detected in prostate cancer, responsible for driving carcinogenesis. The other key role of TMPRSS2 is in priming the viral spike protein which facilitates viral entry essential for viral infectivity. The protease activates a diverse range of viruses. Both SARS-CoV and SARS-CoV-2 (COVID-19) use angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 to facilitate entry to cells, but with SARS-CoV-2 human-to-human transmission is much higher than SARS-CoV. As TMPRSS2 is expressed outside of the lung, and can therefore contribute to extrapulmonary spread of viruses, it warrants further exploration as a potential target for limiting viral spread and infectivity.

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          Most cited references30

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          SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

          Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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            A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells

            Summary The pandemic coronavirus SARS-CoV-2 threatens public health worldwide. The viral spike protein mediates SARS-CoV-2 entry into host cells and harbors a S1/S2 cleavage site containing multiple arginine residues (multibasic) not found in closely related animal coronaviruses. However, the role of this multibasic cleavage site in SARS-CoV-2 infection is unknown. Here, we report that the cellular protease furin cleaves the spike protein at the S1/S2 site and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. Moreover, optimizing the S1/S2 site increased cell-cell, but not virus-cell, fusion, suggesting that the corresponding viral variants might exhibit increased cell-cell spread and potentially altered virulence. Our results suggest that acquisition of a S1/S2 multibasic cleavage site was essential for SARS-CoV-2 infection of humans and identify furin as a potential target for therapeutic intervention.
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              TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes

              Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA are frequently observed in COVID-19 patients. However, it is unclear whether SARS-CoV-2 replicates in the human intestine and contributes to possible fecal-oral transmission. Here, we report productive infection of SARS-CoV-2 in ACE2+ mature enterocytes in human small intestinal enteroids. Expression of two mucosa-specific serine proteases, TMPRSS2 and TMPRSS4, facilitated SARS-CoV-2 spike fusogenic activity and promoted virus entry into host cells. We also demonstrate that viruses released into the intestinal lumen were inactivated by simulated human colonic fluid, and infectious virus was not recovered from the stool specimens of COVID-19 patients. Our results highlight the intestine as a potential site of SARS-CoV-2 replication, which may contribute to local and systemic illness and overall disease progression.
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                Author and article information

                Journal
                J Clin Pathol
                J. Clin. Pathol
                jclinpath
                jcp
                Journal of Clinical Pathology
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0021-9746
                1472-4146
                September 2020
                1 September 2020
                : jclinpath-2020-206987
                Affiliations
                [1] departmentPathology and Molecular Medicine , Wellington School of Medicine and Health Sciences, University of Otago , Wellington, New Zealand
                Author notes
                [Correspondence to ] Dr Michelle Thunders, Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, University of Otago, Wellington 6242, New Zealand; michelle.thunders@ 123456otago.ac.nz
                Author information
                http://orcid.org/0000-0001-6722-7072
                http://orcid.org/0000-0002-5398-0300
                Article
                jclinpath-2020-206987
                10.1136/jclinpath-2020-206987
                7470178
                32873700
                a682a446-2458-48bc-97c7-7df17536e7b5
                © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

                This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

                History
                : 13 August 2020
                Categories
                Gene of the Month
                2474
                1531
                2478
                Custom metadata
                free
                true

                Pathology
                genetics,prostate,carcinoma,virology,enzymes
                Pathology
                genetics, prostate, carcinoma, virology, enzymes

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