Macrophage migration inhibitory factor (MIF) acetylation protects neurons from ischemic injury.
Macrophage migration inhibitory factor (MIF) acetylation protects neurons from ischemic injury.
复制标题
巨噬细胞迁移抑制因子（MIF）乙酰化保护神经元免受缺血性损伤
DOI：
10.1038/s41419-022-04918-2
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发表时间：
2022-05-18
影响因子：
9
通讯作者：
Li, Lei
中科院分区：
文献类型：
--
作者：
Hu, Jin-Xia;Ma, Wei-Jing;He, Li-Ying;Zhang, Cong-Hui;Zhang, Cheng;Wang, Yan;Chen, Chao-Nan;Shen, Da-Yong;Gao, Hui-Min;Guo, Rui-Ru;Ning, Qian-Qian;Ye, Xin-Chun;Cui, Gui-Yun;Li, Lei
缺血诱导的神经元死亡会导致缺血性中风患者终生严重的神经功能缺陷。组蛋白去乙酰化酶6（HDAC 6）是一个有前途的目标，在许多神经系统疾病，包括缺血性中风的神经保护。然而，HDAC 6抑制在缺血性中风后保护神经元的机制仍不清楚。在这里，我们发现HDAC 6的基因消融或药物抑制通过增加巨噬细胞移动抑制因子（MIF）乙酰化来减少缺血性卒中后的脑损伤。质谱分析和生化结果表明，HDAC 6抑制剂或阿司匹林处理促进K78残基上的MIF乙酰化。MIF K78乙酰化抑制了MIF和AIF之间的相互作用，从而阻碍了缺血皮层神经元中MIF向核的移位。此外，在MIF K78 Q突变小鼠缺血后，皮层神经元DNA断裂和神经元死亡受损。我们的研究结果表明，HDAC 6抑制和阿司匹林治疗的神经保护作用来自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系统疾病的治疗靶点。
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.
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影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
影响因子：
16.2
作者：
Israelson, Adrian;Ditsworth, Dara;Sun, Shuying;Song, SungWon;Liang, Jason;Hruska-Plochan, Marian;McAlonis-Downes, Melissa;Abu-Hamad, Salah;Zoltsman, Guy;Shani, Tom;Maldonado, Marcus;Bui, Anh;Navarro, Michael;Zhou, Huilin;Marsala, Martin;Kaspar, Brian K.;Da Cruz, Sandrine;Cleveland, Don W.
通讯作者：
Cleveland, Don W.
DOI：
10.1073/pnas.56.1.72
发表时间：
1966-01-01
影响因子：
11.1
作者：
DAVID, JR
通讯作者：
DAVID, JR
DOI：
10.1073/pnas.51.5.786
发表时间：
1964-01-01
影响因子：
11.1
作者：
ALLFREY, VG;FAULKNER, R;MIRSKY, AE
通讯作者：
MIRSKY, AE