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

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.