Histone deacetylase 7 activates 6-phosphogluconate dehydrogenase via an enzyme-independent mechanism that involves the N-terminal protein-protein interaction domain.

IF 4.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yizhuo Wang, James E B Curson, Divya Ramnath, Kaustav Das Gupta, Robert C Reid, Denuja Karunakaran, David P Fairlie, Matthew J Sweet
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引用次数: 0

Abstract

Histone deacetylase 7 (HDAC7) is a member of the class IIa family of classical HDACs with important roles in cell development, differentiation, and activation, including in macrophages and other innate immune cells. HDAC7 and other class IIa HDACs act as transcriptional repressors in the nucleus but, in some cell types, they can also act in the cytoplasm to modify non-nuclear proteins and/or scaffold signalling complexes. In macrophages, HDAC7 is a cytoplasmic protein with both pro- and anti-inflammatory functions, with the latter activity involving activation of the pentose phosphate pathway (PPP) enzyme 6-phosphogluconate dehydrogenase (6PGD) and the generation of anti-inflammatory metabolite ribulose-5-phosphate. Here, we used ectopic expression systems and biochemical approaches to investigate the mechanism by which HDAC7 promotes 6PGD enzyme activity. We reveal that HDAC7 enzyme activity is not required for its activation of 6PGD and that the N-terminal protein-protein interaction domain of HDAC7 is sufficient to initiate this response. Mechanistically, the N-terminus of HDAC7 increases the affinity of 6PGD for NADP+, promotes the generation of a shorter form of 6PGD, and enhances the formation of higher order protein complexes, implicating its scaffolding function in engagement of the PPP. This contrasts with the pro-inflammatory function of HDAC7 in macrophages, in which it promotes deacetylation of the glycolytic enzyme pyruvate kinase M2 for inflammatory cytokine production.

组蛋白去乙酰化酶 7 通过一种与酶无关的机制激活 6-磷酸葡萄糖酸脱氢酶,该机制涉及 N 端蛋白-蛋白相互作用结构域。
组蛋白去乙酰化酶 7(HDAC7)是经典 HDAC IIa 类家族的成员,在细胞发育、分化和活化(包括巨噬细胞和其他先天性免疫细胞)中发挥着重要作用。HDAC7 和其他 IIa 类 HDAC 在细胞核中充当转录抑制因子,但在某些细胞类型中,它们也能在细胞质中改变非核蛋白和/或支架信号复合物。在巨噬细胞中,HDAC7是一种细胞质蛋白,具有促炎和抗炎两种功能,后者的活性涉及激活磷酸戊糖途径(PPP)酶6-磷酸葡萄糖酸脱氢酶(6PGD)和生成抗炎代谢产物核酮糖-5-磷酸。在这里,我们利用异位表达系统和生化方法研究了 HDAC7 促进 6PGD 酶活性的机制。我们发现,HDAC7 激活 6PGD 并不需要 HDAC7 的酶活性,HDAC7 的 N 端蛋白-蛋白相互作用结构域足以启动这一反应。从机理上讲,HDAC7 的 N 端增加了 6PGD 对 NADP+ 的亲和力,促进了较短形式 6PGD 的生成,并增强了高阶蛋白复合物的形成,这意味着它在参与 PPP 过程中的支架功能。这与 HDAC7 在巨噬细胞中的促炎功能形成鲜明对比,在巨噬细胞中,HDAC7 促进糖酵解酶丙酮酸激酶 M2 的去乙酰化,从而产生炎性细胞因子。
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来源期刊
Biochemical Journal
Biochemical Journal 生物-生化与分子生物学
CiteScore
8.00
自引率
0.00%
发文量
255
审稿时长
1 months
期刊介绍: Exploring the molecular mechanisms that underpin key biological processes, the Biochemical Journal is a leading bioscience journal publishing high-impact scientific research papers and reviews on the latest advances and new mechanistic concepts in the fields of biochemistry, cellular biosciences and molecular biology. The Journal and its Editorial Board are committed to publishing work that provides a significant advance to current understanding or mechanistic insights; studies that go beyond observational work using in vitro and/or in vivo approaches are welcomed. Painless publishing: All papers undergo a rigorous peer review process; however, the Editorial Board is committed to ensuring that, if revisions are recommended, extra experiments not necessary to the paper will not be asked for. Areas covered in the journal include: Cell biology Chemical biology Energy processes Gene expression and regulation Mechanisms of disease Metabolism Molecular structure and function Plant biology Signalling
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