Role of BET Proteins in Inflammation and CNS Diseases

Abstract

Bromodomain and extra-terminal domain (BET) proteins consist of four mammalian members (BRD2, BRD3, BRD4, and BRDT), which play a pivotal role in the transcriptional regulation of the inflammatory response. Dysregulated inflammation is a key pathological process in various CNS disorders through multiple mechanisms, including NF-κB and Nrf2 pathways, two well-known master regulators of inflammation. A better mechanistic understanding of the BET proteins' role in regulating the inflammatory process is of great significance since it could reveal novel therapeutic targets to reduce neuroinflammation associated with many CNS diseases. In this minireview, we first outline the structural features of BET proteins and summarize genetic and pharmacological approaches for BET inhibition, including novel strategies using proteolysis-targeting chimeras (PROTACs). We emphasize in vitro and in vivo evidence of the interplay between BET proteins and NF-κB and Nrf2 signaling pathways. Finally, we summarize recent studies showing that BET proteins are essential regulators of inflammation and neuropathology in various CNS diseases.

Keywords: Alzheimer’s disease; multiple sclerosis; neuroinflammation; neurological diseases; proteolysis-targeting chimera; seizure; spinal cord injury; stroke.

FIGURE 1

Human BET family structural domains and mechanisms of inhibition. (A) Structural domains of BET proteins. All BET proteins share two tandem N-terminal bromodomains (BD1 and BD2) and an extra-terminal (ET) domain. In addition, Brd4 and BrdT contain a unique C-terminal domain (CTD). The numbers refer to the amino acid boundaries of each domain for the human BET proteins. The alignment of amino acid (aa) sequences is from the public protein sequence database, GenPept, NCBI Reference Sequence: Brd2, NP_005095.1; Brd3, NP_031397.1; Brd4, NP_490,597.1; BrdT, NP_001229734.2. (B) To date, all reported BET inhibitors (BETis) target BDs on BET proteins. (C) BET PROTAC mechanism. The E1 enzyme activates ubiquitin (Ub) and initiates its transfer to a target substrate through the E1-E2-E3 cascade. Then, the target substrate tagged by ubiquitin is degraded by the proteasome. Without BET PROTAC, BET protein is not recognizable for the ubiquitination process. BET PROTAC molecules can bind the target BET protein and the E3 ubiquitin ligase together, and such binding ubiquitinates the target protein, making it available for subsequent proteasomal degradation.