TMPRSS2 isoform 1 downregulation by G-quadruplex stabilization induces SARS-CoV-2 replication arrest.
BMC Biol
; 22(1): 5, 2024 01 08.
Article
de En
| MEDLINE
| ID: mdl-38185627
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.Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
SARS-CoV-2
/
COVID-19
Type d'étude:
Prognostic_studies
Limites:
Humans
Langue:
En
Journal:
BMC Biol
Sujet du journal:
BIOLOGIA
Année:
2024
Type de document:
Article
Pays d'affiliation:
Allemagne