Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
Signal Transduct Target Ther. 2021 Jan 19;6(1):23. doi: 10.1038/s41392-020-00384-4.
Innate immunity serves as the rapid and first-line defense against invading pathogens, and this process can be regulated at various levels, including epigenetic mechanisms. The bromodomain and extraterminal domain (BET) family of proteins consists of four conserved mammalian members (BRD2, BRD3, BRD4, and BRDT) that regulate the expression of many immunity-associated genes and pathways. In particular, in response to infection and sterile inflammation, abnormally expressed or dysfunctional BETs are involved in the activation of pattern recognition receptor (e.g., TLR, NLR, and CGAS) pathways, thereby linking chromatin machinery to innate immunity under disease or pathological conditions. Mechanistically, the BET family controls the transcription of a wide range of proinflammatory and immunoregulatory genes by recognizing acetylated histones (mainly H3 and H4) and recruiting transcription factors (e.g., RELA) and transcription elongation complex (e.g., P-TEFb) to the chromatin, thereby promoting the phosphorylation of RNA polymerase II and subsequent transcription initiation and elongation. This review covers the accumulating data about the roles of the BET family in innate immunity, and discusses the attractive prospect of manipulating the BET family as a new treatment for disease.
先天免疫作为抵御入侵病原体的快速和第一线防御，这个过程可以在多个水平上进行调节，包括表观遗传机制。溴结构域和末端结构域（BET）蛋白家族由四个保守的哺乳动物成员（BRD2、BRD3、BRD4 和 BRDT）组成，它们调节许多与免疫相关的基因和途径的表达。特别是，在感染和无菌性炎症反应中，异常表达或功能失调的 BET 参与模式识别受体（如 TLR、NLR 和 CGAS）途径的激活，从而在疾病或病理条件下将染色质机制与先天免疫联系起来。从机制上讲，BET 家族通过识别乙酰化组蛋白（主要是 H3 和 H4）并招募转录因子（如 RELA）和转录延伸复合物（如 P-TEFb）到染色质上来控制广泛的促炎和免疫调节基因的转录，从而促进 RNA 聚合酶 II 的磷酸化以及随后的转录起始和延伸。这篇综述涵盖了 BET 家族在先天免疫中作用的积累数据，并讨论了操纵 BET 家族作为疾病新治疗方法的诱人前景。
