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.

中文翻译：

---

组蛋白脱乙酰酶 7 通过涉及 N 末端蛋白质-蛋白质相互作用结构域的酶非依赖性机制激活 6-磷酸葡萄糖酸脱氢酶。


组蛋白脱乙酰酶 7 （HDAC7） 是经典 HDAC 的 IIa 类家族的成员，在细胞发育、分化和活化中具有重要作用，包括在巨噬细胞和其他先天免疫细胞中。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，它们也可以在细胞质中发挥作用，以修饰非核蛋白和/或支架信号复合物。在巨噬细胞中，HDAC7 是一种具有促炎和抗炎功能的细胞质蛋白，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） 和产生抗炎代谢物核酮糖-5-磷酸。在这里，我们使用异位表达系统和生化方法来研究 HDAC7 促进 6PGD 酶活性的机制。我们揭示了 HDAC7 酶活性不是其激活 6PGD 所必需的，并且 HDAC7 的 N 末端蛋白质-蛋白质相互作用结构域足以启动这种反应。从机制上讲，HDAC7 的 N 端增加了 6PGD 对 NADP+ 的亲和力，促进了更短形式的 6PGD 的产生，并增强了高级蛋白质复合物的形成，表明其在 PPP 参与中的支架功能。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，它促进糖酵解酶丙酮酸激酶 M2 的脱乙酰化以产生炎性细胞因子。