HDAC6 deacetylates ENKD1 to regulate mitotic spindle behavior and corneal epithelial homeostasis.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-03-28 DOI:10.1038/s44319-025-00438-0

Ting Song, Xueqing Han, Hanxiao Yin, Junkui Zhao, Mingming Ma, Xiaonuan Wen, Chunli Liu, Yiyang Yue, Huijie Zhao, Jun Zhou, Yang Yang, Jie Ran, Min Liu

{"title":"HDAC6 deacetylates ENKD1 to regulate mitotic spindle behavior and corneal epithelial homeostasis.","authors":"Ting Song, Xueqing Han, Hanxiao Yin, Junkui Zhao, Mingming Ma, Xiaonuan Wen, Chunli Liu, Yiyang Yue, Huijie Zhao, Jun Zhou, Yang Yang, Jie Ran, Min Liu","doi":"10.1038/s44319-025-00438-0","DOIUrl":null,"url":null,"abstract":"<p><p>Corneal diseases can cause severe visual impairment and even blindness, which have been linked to the interruption of corneal epithelial homeostasis. However, the underlying molecular mechanisms are largely unknown. In this study, by comparing the transcriptomes of keratoconus, bacterial keratitis, viral keratitis, and healthy corneas, we found a steady upregulation of histone deacetylase 6 (HDAC6) in corneal diseases. Consistently, a significant increase in HDAC6 was observed in mouse corneas with bacterial keratitis. Overexpression of HDAC6 in mice results in a significant thickening of the corneal epithelium. Mechanistic studies reveal that HDAC6 overexpression disrupts mitotic spindle orientation and positioning in corneal epithelial cells. Our data further show that HDAC6 deacetylates enkurin domain-containing protein 1 (ENKD1) at lysine 98 and thereby impedes its interaction with γ-tubulin, restraining the centrosomal localization of ENKD1 and its proper function in regulating mitotic spindle behavior. These findings uncover a pivotal role for HDAC6-mediated deacetylation of ENKD1 in the control of corneal epithelial homeostasis, providing potential therapeutic targets for treating corneal diseases.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5000,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"EMBO Reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s44319-025-00438-0","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Corneal diseases can cause severe visual impairment and even blindness, which have been linked to the interruption of corneal epithelial homeostasis. However, the underlying molecular mechanisms are largely unknown. In this study, by comparing the transcriptomes of keratoconus, bacterial keratitis, viral keratitis, and healthy corneas, we found a steady upregulation of histone deacetylase 6 (HDAC6) in corneal diseases. Consistently, a significant increase in HDAC6 was observed in mouse corneas with bacterial keratitis. Overexpression of HDAC6 in mice results in a significant thickening of the corneal epithelium. Mechanistic studies reveal that HDAC6 overexpression disrupts mitotic spindle orientation and positioning in corneal epithelial cells. Our data further show that HDAC6 deacetylates enkurin domain-containing protein 1 (ENKD1) at lysine 98 and thereby impedes its interaction with γ-tubulin, restraining the centrosomal localization of ENKD1 and its proper function in regulating mitotic spindle behavior. These findings uncover a pivotal role for HDAC6-mediated deacetylation of ENKD1 in the control of corneal epithelial homeostasis, providing potential therapeutic targets for treating corneal diseases.

查看原文本刊更多论文

HDAC6使ENKD1去乙酰化，调节有丝分裂纺锤体行为和角膜上皮稳态。

角膜疾病可导致严重的视力损伤，甚至失明，这与角膜上皮平衡被破坏有关。然而，其潜在的分子机制在很大程度上还不为人所知。在这项研究中，通过比较角膜炎、细菌性角膜炎、病毒性角膜炎和健康角膜的转录组，我们发现在角膜疾病中组蛋白去乙酰化酶 6（HDAC6）会稳定上调。同样，在患有细菌性角膜炎的小鼠角膜中也观察到了 HDAC6 的显著增加。在小鼠体内过量表达 HDAC6 会导致角膜上皮明显增厚。机理研究表明，HDAC6 的过表达会破坏角膜上皮细胞有丝分裂纺锤体的定向和定位。我们的数据进一步表明，HDAC6会在赖氨酸98处使含恩库林结构域的蛋白1（ENKD1）去乙酰化，从而阻碍其与γ-微管蛋白的相互作用，抑制ENKD1的中心体定位及其调节有丝分裂纺锤体行为的正常功能。这些发现揭示了 HDAC6 介导的 ENKD1 去乙酰化在控制角膜上皮稳态中的关键作用，为治疗角膜疾病提供了潜在的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.