HDAC3的雙重活性參與調控炎症反應
作者:
小柯機器人發布時間:2020/8/6 19:28:42
美國賓夕法尼亞大學Mitchell A. Lazar課題組發現,組蛋白去乙醯化酶3(HDAC3)雙重活性參與調控炎症反應。2020年8月5日,《自然》在線發表了這一成果。
在本研究中,研究人員發現在脂多糖激活巨噬細胞的過程中,不需要核受體輔抑制因子1和2(NCoR1/2),HDAC3即被招募到激活轉錄因子2(ATF2)的結合位點並通過非經典機制激活炎症基因的表達。相比之下,HDAC3的去乙醯酶活性選擇性地結合在抑制Toll樣受體信號轉導的ATF3結合位點。缺失HDAC3的巨噬細胞可保護小鼠免於脂多糖造成的死亡,但這種保護作用並非通過遺傳或藥理學方法抑制HDAC3的催化活性實現。
該研究表明,HDAC3具有轉錄激活因子和抑制因子的雙重功能,具有不依賴於去乙醯化酶活性的非經典功能,這對先天免疫系統至關重要。
據了解,HDACs是染色質修飾酶的超家族,可通過修飾組蛋白使轉錄沉默。在該家族中,HDAC3的獨特之處在於其需要與NCoR1/2相互作用來發揮催化活性。但是,HDAC3的整體丟失也導致轉錄的抑制,目前尚不清楚其機制。
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