The bromodomain protein BRD4 positively regulates necroptosis via modulating MLKL expression.
Yu XiongLinli LiLiting ZhangYangyang CuiChengyong WuHui LiKai ChenQiuyuan YangRong XiangYiguo HuShile HuangYuquan WeiShengyong YangPublished in: Cell death and differentiation (2019)
Necroptosis is a programmed form of necrotic cell death, which is tightly regulated by the necroptotic signaling pathway containing receptor-interacting protein (RIP)1, RIP3, and mixed-lineage kinase domain-like (MLKL) protein. In addition to the RIP1-RIP3-MLKL axis, other factors regulating necroptosis are still largely unknown. Here a cell-based small-molecule screening led to the finding that BET inhibitors protected cells from necroptosis in the TNFα/Smac-mimetic/Z-VAD-FMK (TSZ)-induced cell necroptosis model. Mechanistic studies revealed that BET inhibitors acted by downregulating MLKL expression. Further research demonstrated that BRD4, IRF1, P-TEFb, and RNA polymerase II formed a transcription complex to regulate the expression of MLKL, and BET inhibitors interfered with the transcription complex formation. In necroptosis-related disease model, the BET inhibitor JQ-1 showed promising therapeutic effects. Collectively, our studies establish, for the first time, BRD4 as a new epigenetic factor regulating necroptosis, and highlight the potential of BET inhibitors in the treatment of necroptosis-related diseases.
Keyphrases
- poor prognosis
- small molecule
- binding protein
- signaling pathway
- single cell
- cell death
- protein protein
- transcription factor
- cell therapy
- gene expression
- amino acid
- dna methylation
- long non coding rna
- risk assessment
- dendritic cells
- pi k akt
- protein kinase
- oxidative stress
- high glucose
- climate change
- human health
- tyrosine kinase
- cell fate
- light emitting