ABSTRACT
Bromodomain and extra-terminal (BET) proteins are relevant chromatin adaptors involved in the transcriptional control of thousands of genes. Two tandem N-terminal bromodomains are essential for chromatin attachment through acetyl-histone recognition. Recently, the BET proteins members BRD2 and BRD4 were found to interact with the SARS-CoV-2 envelope (E) protein, raising the question of whether the interaction constitutes a virus hijacking mechanism for transcription alteration in the host cell. To shed light on this question, we have compared the transcriptome of cells overexpressing E with that of cells treated with the BET inhibitor JQ1. Notably, E overexpression leads to a strong upregulation of natural immunity- and interferon response-related genes. However, BET inhibition results in the downregulation of most of these genes, indicating that these two conditions, far from causing a significant overlap of the altered transcriptomes, course with quite different outputs. Concerning the interaction of E protein with BET members, and differing from previous reports indicating that it occurs through BET bromodomains, we find that it relies on SEED and SEED-like domains, BET regions rich in Ser, Asp, and Glu residues. By taking advantage of this specific interaction, we have been able to direct selective degradation of E protein through a PROTAC system involving a dTAG-SEED fusion, highlighting the possible therapeutic use of this peptide for targeted degradation of a viral essential protein.
Subject(s)
Cell Cycle Proteins , SARS-CoV-2 , Transcription Factors , Triazoles , Humans , Transcription Factors/metabolism , Transcription Factors/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Triazoles/pharmacology , Azepines/pharmacology , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Protein Domains , Transcription, Genetic/drug effects , COVID-19/virology , COVID-19/metabolism , HEK293 Cells , Protein Binding , Bromodomain Containing ProteinsABSTRACT
Diabetes (T2DM) is a major global health issue, and developing new approaches to its prevention is of paramount importance. We hypothesized that abnormalities in lipid metabolism are involved in alpha-cell deregulation. We therefore studied the metabolic factors underlying alpha-cell dysfunction in T2DM progression after a dietary intervention (Mediterranean and low-fat). Additionally, we evaluated whether postprandial glucagon levels may be considered as a predictive factor of T2DM in cardiovascular patients. Non-T2DM participants from the CORDIOPREV study were categorized by tertiles of the area under the curve (AUC) for triacylglycerols and also by tertiles of AUC for glucagon. Our results showed that patients with higher triacylglycerols levels presented elevated postprandial glucagon (P = 0.009). Moreover, we observed higher risk of T2DM (hazard ratio: 2.65; 95% confidence interval: 1.56-4.53) in subjects with elevated glucagon. In conclusion, high postprandial lipemia may induce alpha-cell dysfunction in cardiovascular patients. Our results also showed that postprandial glucagon levels could be used to predict T2DM development.