FYCO1 regulates autophagy and senescence via PAK1/p21 in cataract

Shuying Chen; Wei Zhao; Rongrong Chen; Feiyin Sheng; Yuzhou Gu; Shengjie Hao; Di Wu; Bing Lu; Lu Chen; Yuhao Wu; Yili Xu; Yu Han; Lei Zhou; S Amer Riazuddin; Qiuli Fu; Ke Yao

doi:10.1016/j.abb.2024.110180

FYCO1 regulates autophagy and senescence via PAK1/p21 in cataract

Arch Biochem Biophys. 2024 Oct 10:110180. doi: 10.1016/j.abb.2024.110180. Online ahead of print.

Authors

Shuying Chen¹, Wei Zhao², Rongrong Chen¹, Feiyin Sheng¹, Yuzhou Gu¹, Shengjie Hao¹, Di Wu¹, Bing Lu¹, Lu Chen¹, Yuhao Wu¹, Yili Xu¹, Yu Han¹, Lei Zhou³, S Amer Riazuddin⁴, Qiuli Fu⁵, Ke Yao⁶

Affiliations

¹ Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China.
² Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China; Eye department, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University.
³ School of Optometry, Department of Applied Biology and Chemical Technology, Research Centre for SHARP Vision (RCSV), The Hong Kong Polytechnic University, Hong Kong; Centre for Eye and Vision Research (CEVR), 17W Hong Kong Science Park, Hong Kong.
⁴ The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China. Electronic address: 2313009@zju.edu.cn.
⁶ Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China. Electronic address: xlren@zju.edu.cn.

PMID: 39395618
DOI: 10.1016/j.abb.2024.110180

Abstract

Background: ARC (Age-related cataract) is one of the leading causes of vision impairment and blindness; however, its pathogenesis remains unclear. FYCO1 (FYVE and coiled-coil domain containing 1) serves as an autophagy adaptor. The present study investigated the role of FYCO1 in cataract.

Methods: Ultraviolet-B (UVB) irradiation was used to establish a cataract mice model. Hematoxylin and eosin (H&E) assay were used to observe lens morphology. Cell models were constructed by cultivating SRA 01/04 cells with H₂O₂ and UVB. Cell counting kit-8 (CCK8) and Senescence-associated β-galactosidase (SA-β-Gal) assay were performed to explore proliferation and senescence. The gene and protein expression were assessed by quantitative real-time PCR (qRT-PCR), western blot and immunofluorescence staining.

Results: We demonstrated lens structural damage and downregulation of FYCO1 in mice with UVB-induced cataracts. In vitro results revealed a deletion in autophagy levels along with the decrease of FYCO1 expression in human lens epithelial cells (HLECs) after H₂O₂ treatment, which was confirmed in vivo. The knockout of FYCO1 in the HLECs did not change basal autophagy and senescence but suppressed HLECs response in the induction of both. Further investigation indicated that FYCO1 knockout inhibited senescence and p21 levels by suppressing the expression of p21 activated kinase 1 (PAK1) in cataract cell models.

Conclusions: This study has newly characterized the role of FYCO1 in UVB-induced cataracts and in oxidative stress, both of which are associated with ARCs. A novel association between FYCO1 and PAK1/p21 in lens epithelial cell autophagy, senescence, and cataractogenesis also appears to have been established.

Keywords: FYCO1; PAK1; age-related cataracts; autophagy; lens epithelial cells; p21; senescence.