Institute of Stroke Research and Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China.
ShanghaiTech University, Shanghai, China.
Cell Death Dis. 2022 May 18;13(5):466. doi: 10.1038/s41419-022-04918-2.
Ischemia-induced neuronal death leads to serious lifelong neurological deficits in ischemic stroke patients. Histone deacetylase 6 (HDAC6) is a promising target for neuroprotection in many neurological disorders, including ischemic stroke. However, the mechanism by which HDAC6 inhibition protects neurons after ischemic stroke remains unclear. Here, we discovered that genetic ablation or pharmacological inhibition of HDAC6 reduced brain injury after ischemic stroke by increasing macrophage migration inhibitory factor (MIF) acetylation. Mass spectrum analysis and biochemical results revealed that HDAC6 inhibitor or aspirin treatment promoted MIF acetylation on the K78 residue. MIF K78 acetylation suppressed the interaction between MIF and AIF, which impaired MIF translocation to the nucleus in ischemic cortical neurons. Moreover, neuronal DNA fragmentation and neuronal death were impaired in the cortex after ischemia in MIF K78Q mutant mice. Our results indicate that the neuroprotective effect of HDAC6 inhibition and aspirin treatment results from MIF K78 acetylation; thus, MIF K78 acetylation may be a therapeutic target for ischemic stroke and other neurological diseases.
缺血性神经元死亡导致缺血性中风患者严重的终身神经功能缺损。组蛋白去乙酰化酶 6（HDAC6）是许多神经疾病包括缺血性中风神经保护的有希望的靶点。然而，HDAC6 抑制在缺血性中风后保护神经元的机制尚不清楚。在这里，我们发现，通过增加巨噬细胞移动抑制因子（MIF）乙酰化，HDAC6 的遗传缺失或药理学抑制减少了缺血性中风后的脑损伤。质谱分析和生化结果表明，HDAC6 抑制剂或阿司匹林治疗促进了 MIF 在 K78 残基上的乙酰化。MIF K78 乙酰化抑制了 MIF 与 AIF 之间的相互作用，从而阻止了 MIF 在缺血性皮质神经元中的核转位。此外，在 MIF K78Q 突变小鼠的皮质中，缺血后神经元 DNA 片段化和神经元死亡受损。我们的结果表明，HDAC6 抑制和阿司匹林治疗的神经保护作用源于 MIF K78 乙酰化；因此，MIF K78 乙酰化可能是缺血性中风和其他神经疾病的治疗靶点。
