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  3. PIKFYVE deficiency induces vacuole-like cataract via perturbing late endosome homeostasis

PIKFYVE deficiency induces vacuole-like cataract via perturbing late endosome homeostasis

  • Biochem Biophys Res Commun. 2025 Feb 2:747:151123. doi: 10.1016/j.bbrc.2024.151123.
Xiaochen Ma 1,  Sejie Yu 2,  Min Zhang 1,  Shaoyi Mei 3,  Yunzhi Ling 4,  Xiaosheng Huang 3,  Songguo Dong 3,  Baojian Fan 5,  Jun Zhao 6
Affiliations

Affiliations

  • 1 The Second Clinical Medical College of Jinan University, Department of Ophthalmology, Shenzhen People's Hospital, Shenzhen, 518020, Guangdong, China.
  • 2 Department of Ophthalmology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.
  • 3 Shenzhen Eye Institute, Shenzhen Eye Hospital Affiliated to Jinan University, Shenzhen, China.
  • 4 Department of Dermatology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China.
  • 5 Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: bfan@mgh.harvard.edu.
  • 6 Department of Ophthalmology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China. Electronic address: doctorzhaojun@163.com.
PMID: 39778216 DOI: 10.1016/j.bbrc.2024.151123
Abstract

Phosphoinositide kinase, FYVE-type zinc finger containing (PIKfyve) was recently identified as a causative gene for cataract. PIKfyve phosphatidylinositol phosphate kinase domain-deficient (PIKfyveΔ8) zebrafish lens and PIKFYVE-inhibited human lens epithelial cells developed vacuoles, colocalized with late endosome marker RAB7. In this study, the PIKfyveΔ8zebrafish with vacuole-like cataract underwent transcriptomic and proteomic analyses to explore the underlying mechanisms of vacuole formation. PIKFYVE-knockout and PIKFYVE-inhibited human lens epithelial cells with vacuoles further verified these omics results and rescued with Bafilomycin A1(Baf-A1) and U18666A. We discovered no significant differences in lysosomal fusion, but upregulation in acid hydrolase. The composition of late endosomal membrane was changed, and vacuolar ATPase and endosomal sorting complexes required for transport (ESCRT) at late endosome were upregulated. These changes are related with the late endosome homeostasis. Strikingly, vacuoles in human lens epithelial cells could be partially rescued by Baf-A1 and almost completely rescued by U18666A. Collectively, these findings suggest that vacuoles in PIKfyveΔ8 zebrafish lens and PIKFYVE-inhibited cells were colocalized with swollen late endosomes, and generated by perturbing late endosome homeostasis due to enhanced ESCRT mechanisms and decreased stability in late endosomal membrane. This study expands our understanding of the mechanisms underlying cataract development and reveals potentially effective therapeutic targets.

Keywords

Late endosome homeostasis; Lens; PIKFYVE; Proteomics; Transcriptomics; Vacuole.

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