小柯机器人

美国宾夕法尼亚大学Mitchell A. Lazar课题组发现，组蛋白去乙酰化酶3（HDAC3）双重活性参与调控炎症反应。2020年8月5日，《自然》在线发表了这一成果。

在本研究中，研究人员发现在脂多糖激活巨噬细胞的过程中，不需要核受体辅抑制因子1和2（NCoR1/2），HDAC3即被招募到激活转录因子2（ATF2）的结合位点并通过非经典机制激活炎症基因的表达。相比之下，HDAC3的去乙酰酶活性选择性地结合在抑制Toll样受体信号转导的ATF3结合位点。缺失HDAC3的巨噬细胞可保护小鼠免于脂多糖造成的死亡，但这种保护作用并非通过遗传或药理学方法抑制HDAC3的催化活性实现。

该研究表明，HDAC3具有转录激活因子和抑制因子的双重功能，具有不依赖于去乙酰化酶活性的非经典功能，这对先天免疫系统至关重要。

据了解，HDACs是染色质修饰酶的超家族，可通过修饰组蛋白使转录沉默。在该家族中，HDAC3的独特之处在于其需要与NCoR1/2相互作用来发挥催化活性。但是，HDAC3的整体丢失也导致转录的抑制，目前尚不清楚其机制。

附：英文原文

Title: Dichotomous engagement of HDAC3 activity governs inflammatory responses

Author: Hoang C. B. Nguyen, Marine Adlanmerini, Amy K. Hauck, Mitchell A. Lazar

Issue&Volume: 2020-08-05

Abstract: The histone deacetylases (HDACs) are a superfamily of chromatin-modifying enzymes that silence transcription through the modification of histones. Among them, HDAC3 is unique in that interaction with nuclear receptor corepressors 1 and 2 (NCoR1/2) is required to engage its catalytic activity1,2,3. However, global loss of HDAC3 also results in the repression of transcription, the mechanism of which is currently unclear4,5,6,7,8. Here we report that, during the activation of macrophages by lipopolysaccharides, HDAC3 is recruited to activating transcription factor 2 (ATF2)-bound sites without NCoR1/2 and activates the expression of inflammatory genes through a non-canonical mechanism. By contrast, the deacetylase activity of HDAC3 is selectively engaged at ATF3-bound sites that suppress Toll-like receptor signalling. Loss of HDAC3 in macrophages safeguards mice from lethal exposure to lipopolysaccharides, but this protection is not conferred upon genetic or pharmacological abolition of the catalytic activity of HDAC3. Our findings show that HDAC3 is a dichotomous transcriptional activator and repressor, with a non-canonical deacetylase-independent function that is vital for the innate immune system.

DOI: 10.1038/s41586-020-2576-2

Source: https://www.nature.com/articles/s41586-020-2576-2

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