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Bromodomain and extraterminal inhibitors block the Epstein-Barr virus lytic cycle at two distinct steps.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2017 Aug 11; Vol. 292 (32), pp. 13284-13295. Date of Electronic Publication: 2017 Jun 06. - Publication Year :
- 2017
-
Abstract
- Lytic infection by the Epstein-Barr virus (EBV) poses numerous health risks, such as infectious mononucleosis and lymphoproliferative disorder. Proteins in the bromodomain and extraterminal (BET) family regulate multiple stages of viral life cycles and provide promising intervention targets. Synthetic small molecules can bind to the bromodomains and disrupt function by preventing recognition of acetylated lysine substrates. We demonstrate that JQ1 and other BET inhibitors block two different steps in the sequential cascade of the EBV lytic cycle. BET inhibitors prevent expression of the viral immediate-early protein BZLF1. JQ1 alters transcription of genes controlled by the host protein BACH1, and BACH1 knockdown reduces BZLF1 expression. BET proteins also localize to the lytic origin of replication (OriLyt) genetic elements, and BET inhibitors prevent viral late gene expression. There JQ1 reduces BRD4 recruitment during reactivation to preclude replication initiation. This represents a rarely observed dual mode of action for drugs.
- Subjects :
- Acetylation
Azepines pharmacology
Basic-Leucine Zipper Transcription Factors chemistry
Basic-Leucine Zipper Transcription Factors genetics
Basic-Leucine Zipper Transcription Factors metabolism
Cell Cycle Proteins
Cell Line
Fanconi Anemia Complementation Group Proteins chemistry
Fanconi Anemia Complementation Group Proteins genetics
Fanconi Anemia Complementation Group Proteins metabolism
Herpesvirus 4, Human physiology
Host-Pathogen Interactions drug effects
Humans
Lysine metabolism
Nuclear Proteins chemistry
Nuclear Proteins genetics
Nuclear Proteins metabolism
Protein Interaction Domains and Motifs
Protein Processing, Post-Translational
Protein Transport drug effects
RNA Interference
Replication Origin drug effects
Trans-Activators chemistry
Trans-Activators genetics
Trans-Activators metabolism
Transcription Factors chemistry
Transcription Factors genetics
Transcription Factors metabolism
Triazoles pharmacology
Viral Proteins chemistry
Viral Proteins genetics
Viral Proteins metabolism
Virus Activation drug effects
Virus Physiological Phenomena drug effects
Antiviral Agents pharmacology
Basic-Leucine Zipper Transcription Factors antagonists & inhibitors
Fanconi Anemia Complementation Group Proteins antagonists & inhibitors
Gene Expression Regulation, Viral drug effects
Herpesvirus 4, Human drug effects
Nuclear Proteins antagonists & inhibitors
Trans-Activators antagonists & inhibitors
Transcription Factors antagonists & inhibitors
Viral Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 292
- Issue :
- 32
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28588024
- Full Text :
- https://doi.org/10.1074/jbc.M116.751644