HDAC5 deacetylates cytosolic ACTN4 during skin reepithelialization and represents a therapeutic target for chronic wound healing

组蛋白脱乙酰基酶5 调解人 伤口愈合 细胞生物学 胞浆 乙酰化 癌症研究 组蛋白脱乙酰基酶 化学 药理学 组蛋白 组蛋白H3 人体皮肤 条件基因敲除 转录组 细胞质 医学 HDAC3型 生物 HDAC11型 免疫学 HDAC8型 离体
作者
Yifan Zhang,Dongsheng Wen,Chiakang Ho,Yangdan Liu,Xin Wang,Zhiyuan Zhou,Ya Gao,Qingfeng Li
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science]
卷期号:17 (830): eads0594-eads0594
标识
DOI:10.1126/scitranslmed.ads0594
摘要

Skin repair after injury is a complex multistage process. Reepithelialization is a vital component of skin wound healing and involves intricate molecular regulations that are still not fully understood. Here, using a combination of human tissue and animal models, we identified histone deacetylase 5 (HDAC5) as a key mediator of reepithelialization through a mechanism involving nucleocytoplasmic shuttling to regulate deacetylation of a nonhistone protein. We conducted functional validation through a conditional gene knockout mouse model. In addition, parallel studies using ex vivo human skin confirmed that HDAC5 cytoplasmic localization is necessary for efficient wound closure. Liquid chromatography-mass spectrometry of mouse wounds revealed that cytoplasmic HDAC5 interacts with alpha-actinin-4 (ACTN4). Site-directed mutagenesis, immunofluorescence, and luciferase assays demonstrated that HDAC5 deacetylates ACTN4 at the K417 site, allowing nuclear translocation of ACTN4 and subsequent modulation of transcriptional activity of Y-box-binding protein 1 (YBX1). Single-cell transcriptome analysis of mouse wounds revealed cystatin A as a key factor downstream of the HDAC5/ACTN4/YBX1 axis that enhanced reepithelialization and wound healing. We further identified an HDAC5-selective activator, G194-0712, and showed that it improved wound healing in three mouse models of chronic wounds: diabetic wounds, ischemic wounds, and radiation injury. Together, these results highlight a previously unappreciated mechanism involved in skin repair and suggest that HDAC5 activation may hold promise for the treatment of nonhealing skin wounds.
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