TMPRSS2 isoform 1 downregulation by G-quadruplex stabilization induces SARS-CoV-2 replication arrest
Abstract Background SARS-CoV-2 infection depends on the host cell factors angiotensin-converting enzyme 2, ACE2, and the transmembrane serinprotease 2, TMPRSS2. Potential inhibitors of these proteins would be ideal targets against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) inf...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | BMC Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12915-023-01805-w |
| _version_ | 1797355497413672960 |
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| author | Alessio De Magis Philipp Schult Antonia Schönleber Rebecca Linke Kerstin U. Ludwig Beate M. Kümmerer Katrin Paeschke |
| author_facet | Alessio De Magis Philipp Schult Antonia Schönleber Rebecca Linke Kerstin U. Ludwig Beate M. Kümmerer Katrin Paeschke |
| author_sort | Alessio De Magis |
| collection | DOAJ |
| description | Abstract Background SARS-CoV-2 infection depends on the host cell factors angiotensin-converting enzyme 2, ACE2, and the transmembrane serinprotease 2, TMPRSS2. Potential inhibitors of these proteins would be ideal targets against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. Our data opens the possibility that changes within TMPRSS2 can modulate the outcome during a SARS-CoV-2 infection. Results We reveal that TMPRSS2 acts not only during viral entry but has also an important role during viral replication. In addition to previous functions for TMPRSS2 during viral entry, we determined by specific downregulation of distinct isoforms that only isoform 1 controls and supports viral replication. G-quadruplex (G4) stabilization by chemical compounds impacts TMPRSS2 gene expression. Here we extend and in-depth characterize these observations and identify that a specific G4 in the first exon of the TMPRSS2 isoform 1 is particular targeted by the G4 ligand and affects viral replication. Analysis of potential single nucleotide polymorphisms (SNPs) reveals that a reported SNP at this G4 in isoform 1 destroys the G4 motif and makes TMPRSS2 ineffective towards G4 treatment. Conclusion These findings uncover a novel mechanism in which G4 stabilization impacts SARS-CoV-2 replication by changing TMPRSS2 isoform 1 gene expression. |
| first_indexed | 2024-03-08T14:12:01Z |
| format | Article |
| id | doaj.art-482e5826db224a729a72cbb3f46861e9 |
| institution | Directory Open Access Journal |
| issn | 1741-7007 |
| language | English |
| last_indexed | 2024-03-08T14:12:01Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Biology |
| spelling | doaj.art-482e5826db224a729a72cbb3f46861e92024-01-14T12:36:32ZengBMCBMC Biology1741-70072024-01-0122111810.1186/s12915-023-01805-wTMPRSS2 isoform 1 downregulation by G-quadruplex stabilization induces SARS-CoV-2 replication arrestAlessio De Magis0Philipp Schult1Antonia Schönleber2Rebecca Linke3Kerstin U. Ludwig4Beate M. Kümmerer5Katrin Paeschke6Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital BonnInstitute of Clinical Chemistry and Clinical Pharmacology, University Hospital BonnInstitute of Clinical Chemistry and Clinical Pharmacology, University Hospital BonnInstitute of Clinical Chemistry and Clinical Pharmacology, University Hospital BonnInstitute of Human Genetics, University Hospital BonnInstitute of Virology, University Hospital BonnInstitute of Clinical Chemistry and Clinical Pharmacology, University Hospital BonnAbstract Background SARS-CoV-2 infection depends on the host cell factors angiotensin-converting enzyme 2, ACE2, and the transmembrane serinprotease 2, TMPRSS2. Potential inhibitors of these proteins would be ideal targets against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. Our data opens the possibility that changes within TMPRSS2 can modulate the outcome during a SARS-CoV-2 infection. Results We reveal that TMPRSS2 acts not only during viral entry but has also an important role during viral replication. In addition to previous functions for TMPRSS2 during viral entry, we determined by specific downregulation of distinct isoforms that only isoform 1 controls and supports viral replication. G-quadruplex (G4) stabilization by chemical compounds impacts TMPRSS2 gene expression. Here we extend and in-depth characterize these observations and identify that a specific G4 in the first exon of the TMPRSS2 isoform 1 is particular targeted by the G4 ligand and affects viral replication. Analysis of potential single nucleotide polymorphisms (SNPs) reveals that a reported SNP at this G4 in isoform 1 destroys the G4 motif and makes TMPRSS2 ineffective towards G4 treatment. Conclusion These findings uncover a novel mechanism in which G4 stabilization impacts SARS-CoV-2 replication by changing TMPRSS2 isoform 1 gene expression.https://doi.org/10.1186/s12915-023-01805-wSARS-CoV-2TMPRSS2Secondary DNA structuresG-quadruplexViral replication |
| spellingShingle | Alessio De Magis Philipp Schult Antonia Schönleber Rebecca Linke Kerstin U. Ludwig Beate M. Kümmerer Katrin Paeschke TMPRSS2 isoform 1 downregulation by G-quadruplex stabilization induces SARS-CoV-2 replication arrest BMC Biology SARS-CoV-2 TMPRSS2 Secondary DNA structures G-quadruplex Viral replication |
| title | TMPRSS2 isoform 1 downregulation by G-quadruplex stabilization induces SARS-CoV-2 replication arrest |
| title_full | TMPRSS2 isoform 1 downregulation by G-quadruplex stabilization induces SARS-CoV-2 replication arrest |
| title_fullStr | TMPRSS2 isoform 1 downregulation by G-quadruplex stabilization induces SARS-CoV-2 replication arrest |
| title_full_unstemmed | TMPRSS2 isoform 1 downregulation by G-quadruplex stabilization induces SARS-CoV-2 replication arrest |
| title_short | TMPRSS2 isoform 1 downregulation by G-quadruplex stabilization induces SARS-CoV-2 replication arrest |
| title_sort | tmprss2 isoform 1 downregulation by g quadruplex stabilization induces sars cov 2 replication arrest |
| topic | SARS-CoV-2 TMPRSS2 Secondary DNA structures G-quadruplex Viral replication |
| url | https://doi.org/10.1186/s12915-023-01805-w |
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