Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Oct 17;14(10):2274.
doi: 10.3390/v14102274.

Viral Hijacking of BET Proteins

Irene P Chen  1   2 , Melanie Ott  1   2   3
Affiliations
Review

Viral Hijacking of BET Proteins

Irene P Chen et al. Viruses. .

Abstract

Proteins of the bromodomain and exterminal domain (BET) family mediate critical host functions such as cell proliferation, transcriptional regulation, and the innate immune response, which makes them preferred targets for viruses. These multidomain proteins are best known as transcriptional effectors able to read acetylated histone and non-histone proteins through their tandem bromodomains. They also contain other short motif-binding domains such as the extraterminal domain, which recognizes transcriptional regulatory proteins. Here, we describe how different viruses have evolved to hijack or disrupt host BET protein function through direct interactions with BET family members to support their own propagation. The network of virus-BET interactions emerges as highly intricate, which may complicate the use of small-molecule BET inhibitors-currently in clinical development for the treatment of cancer and cardiovascular diseases-to treat viral infections.

Keywords: BET inhibitors; BET proteins; BRD4; Coronavirus; Flavivirus; Hepatitis B virus; Herpesvirus; JQ1; Papillomavirus; Polyomavirus; RVX-208; Retrovirus; host-pathogen interactions.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
BET protein family members. BRDT, BRD2, BRD3, and BRD4 are the four mammalian members of this family. The main functional domains and their amino acid positions are indicated: BD1 (bromodomain 1), BD2 (bromodomain 2), ET (extraterminal domain), PID (P-TEFb interacting domain), BID (basic residue-enriched domain), NPS (N-terminal phosphorylation site), and CPS (C-terminal phosphorylation site). Horizontal lines span the regions of BRD4 that directly interact with the viruses described in this review; note however that other BET proteins can also interact with viruses. See Table 1 for more information.
Figure 2
Figure 2
Steps in a generic viral life cycle where BET proteins are involved. Many viruses interact with BET family members to mediate viral processes (A–D) and disrupt cellular transcription for their own benefit (E). (A) Integration site selection of MLV, a gammaretrovirus, is facilitated by an interaction between its viral IN protein and BET proteins, leading to integration into genomic regions associated with BET proteins. (B) PV, herpesviruses, and polyomaviruses take advantage of the association of BET proteins to host chromosomes to maintain their viral genomes in infected cells. (C) Certain herpesviruses (EBV and HSV), PV, HBV, and polyomaviruses recruit the BRD4:P-TEFb complex to facilitate viral transcription, while retroviruses encode viral proteins that directly bind the PID of BRD4 to redirect host transcriptional machinery to the viral genes. (D) Herpesviruses and polyomaviruses recruit BRD4 along with other host replication machinery, such as RFC or DNA polymerase δ, facilitate genome replication at their replication foci. (E) PV, Herpesviruses, SARS-CoV-2, and flaviviruses interact with BET proteins to disrupt homeostatic gene transcriptional programs controlled by BET proteins during infection to generate a cell state more favorable to viral replication and virus-induced carcinogenesis.
See this image and copyright information in PMC

References

    1. Kulikowski E., Rakai B.D., Wong N.C.W. Inhibitors of Bromodomain and Extra-Terminal Proteins for Treating Multiple Human Diseases. Med. Res. Rev. 2021;41:223–245. doi: 10.1002/med.21730. - DOI - PMC - PubMed
    1. Patel K., Solomon P.D., Walshe J.L., Ford D.J., Wilkinson-White L., Payne R.J., Low J.K.K., Mackay J.P. BET-Family Bromodomains Can Recognize Diacetylated Sequences from Transcription Factors Using a Conserved Mechanism. Biochemistry. 2021;60:648–662. doi: 10.1021/acs.biochem.0c00816. - DOI - PubMed
    1. Lambert J.-P., Picaud S., Fujisawa T., Hou H., Savitsky P., Uusküla-Reimand L., Gupta G.D., Abdouni H., Lin Z.-Y., Tucholska M., et al. Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains. Mol. Cell. 2019;73:621–638.e17. doi: 10.1016/j.molcel.2018.11.006. - DOI - PMC - PubMed
    1. Dhalluin C., Carlson J.E., Zeng L., He C., Aggarwal A.K., Zhou M.M. Structure and Ligand of a Histone Acetyltransferase Bromodomain. Nature. 1999;399:491–496. doi: 10.1038/20974. - DOI - PubMed
    1. Josling G.A., Selvarajah S.A., Petter M., Duffy M.F. The Role of Bromodomain Proteins in Regulating Gene Expression. Genes. 2012;3:320–343. doi: 10.3390/genes3020320. - DOI - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources