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

被引：0

作者：

Song, Ting ^{[1
]}

Han, Xueqing ^{[1
]}

Yin, Hanxiao ^{[2
]}

Zhao, Junkui ^{[2
]}

Ma, Mingming ^{[1
]}

Wen, Xiaonuan ^{[1
]}

Liu, Chunli ^{[1
]}

Yue, Yiyang ^{[1
]}

Zhao, Huijie ^{[1
]}

Zhou, Jun ^{[1
,2
]}

Yang, Yang ^{[3
]}

Ran, Jie ^{[1
]}

Liu, Min ^{[1
,4
]}

机构：

[1] Shandong Normal Univ, Coll Life Sci, Ctr Cell Struct & Funct, Shandong Prov Key Lab Anim Resistance Biol, Jinan 250014, Peoples R China

[2] Nankai Univ, Coll Life Sci, Dept Genet & Cell Biol, State Key Lab Med Chem Biol, Tianjin 300071, Peoples R China

[3] Zhengzhou Univ, Affiliated Hosp 1, Translat Med Ctr, Zhengzhou 450052, Peoples R China

[4] Haihe Lab Cell Ecosyst, Lab Tissue Homeostasis, Tianjin 300462, Peoples R China

来源：

EMBO REPORTS | 2025年

基金：

中国国家自然科学基金;

关键词：

Spindle Orientation; Spindle Positioning; Centrosome; Deacetylation; Corneal Epithelium;

D O I：

10.1038/s44319-025-00438-0

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 gamma-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.

引用

页码：2597 / 2621

页数：25

共 57 条

[11] Elliott G., O'Hare P., Herpes simplex virus type 1 tegument protein VP22 induces the stabilization and hyperacetylation of microtubules, J Virol, 72, pp. 6448-6455, (1998)
[12] Fung E., Richter C., Yang H.B., Schaffer I., Fischer R., Kessler B.M., Bassermann F., D'Angiolella V., FBXL13 directs the proteolysis of CEP192 to regulate centrosome homeostasis and cell migration, EMBO Rep, 19, (2018)
[13] Griffith M., Alarcon E.I., Brunette I., Regenerative approaches for the cornea, J Intern Med, 280, pp. 276-286, (2016)
[14] Gupta V.K., Chaudhuri O., Mechanical regulation of cell-cycle progression and division, Trends Cell Biol, 32, pp. 773-785, (2022)
[15] Hoffmann I., Centrosomes in mitotic spindle assembly and orientation, Curr Opin Struct Biol, 66, pp. 193-198, (2021)
[16] Kalinski A.L., Kar A.N., Craver J., Tosolini A.P., Sleigh J.N., Lee S.J., Hawthorne A., Brito-Vargas P., Miller-Randolph S., Passino R., Et al., Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition, J Cell Biol, 218, pp. 1871-1890, (2019)
[17] Kozgunova E., Yoshida M.W., Reski R., Goshima G., Spindle motility skews division site determination during asymmetric cell division in Physcomitrella, Nat Commun, 13, (2022)
[18] Lafarga V., Aymerich I., Tapia O., Mayor F., Penela P., A novel GRK2/HDAC6 interaction modulates cell spreading and motility, EMBO J, 31, pp. 856-869, (2012)
[19] Lapp T., Kammrath Betancor P., Schlunck G., Auw-Hadrich C., Maier P., Lange C., Reinhard T., Wolf J., Gene Expression Omnibus GSE, (2023)
[20] Lapp T., Kammrath Betancor P., Schlunck G., Auw-Hadrich C., Maier P., Lange C., Reinhard T., Wolf J., Transcriptional profiling specifies the pathogen-specific human host response to infectious keratitis, Front Cell Infect Microbiol, 13, (2023)

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