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.

Targeted BRD4 protein degradation by dBET1 ameliorates acute ischemic brain injury and improves functional outcomes associated with reduced neuroinflammation and oxidative stress and preservation of blood–brain barrier integrity

“…To date, recognition for the roles of BRD4 in neurological conditions is limited [ 5 ]. Because PROTAC molecule dBET1 contains a BET bromodomain binding moiety JQ1 with much higher selectivity and affinity for BRD4 than other BET members, BRD4 functional regulation is the primary effect of dBET1 [ 5 , 42 – 44 ]. PROTAC technique is a leading strategy for targeting protein degradation through the ubiquitin proteosome system.…”

“…Substantial evidence shows that several pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, as well as other potential cytotoxic molecules, are released in response to ischemic insults [ 46 ]. Previous reports showed that JQ1-treated animals exhibit a marked reduction in the expression of pro-inflammatory mediators IL-1β, IL-6, IL-17, IL-18, and TNF-α in the brain in rodent ischemic stroke models [ 5 , 47 ]. Emerging evidence suggests that BRD4 may act as a critical transcriptional regulator of NF-κB-dependent inflammatory gene expression, such as CCL2, CXCL1, and CXCL10 [ 5 ].…”

“…Previous reports showed that JQ1-treated animals exhibit a marked reduction in the expression of pro-inflammatory mediators IL-1β, IL-6, IL-17, IL-18, and TNF-α in the brain in rodent ischemic stroke models [ 5 , 47 ]. Emerging evidence suggests that BRD4 may act as a critical transcriptional regulator of NF-κB-dependent inflammatory gene expression, such as CCL2, CXCL1, and CXCL10 [ 5 ]. The interaction between BRD4 protein and the NF-κB pathway will be explored in our near future study, which will further elucidate BRD4-dependent molecular mechanisms contributing to neurovascular damage in stroke.…”

“…The effect of dBET1 on oxidative stress could be associated with Nrf2 signaling and its target genes. BET proteins were recently reported as Nrf2 signaling repressors, which involves Keap1-dependent regulation and Keap1-independent regulation [ 5 , 13 , 50 ]. Additional studies are necessary to further our understanding of the complex biology of BET proteins and their crosstalk with the Nrf2 pathway.…”

“…Bromodomain-containing protein 4 (BRD4) is a member of the bromodomain and extra-terminal domain (BET) protein family that is widely distributed throughout the body [ 5 , 6 ]. Recent structural and chemical analyses of BRD4 and its inhibition studies indicate a critical role of BRD4 in coordinating inflammatory and oxidative processes in response to different insults, including ischemia [ 5 , 7 – 10 ]. These works include the identification of JQ1, a first-generation, potent, and selective BRD4 inhibitor [ 6 ].…”