HSP90 stabilizes visual cycle retinol dehydrogenase 5 in the endoplasmic reticulum by inhibiting its degradation during autophagy

Xiaolin Jia; Yuxuan Wang; Mingjun Jiang; Dan-Dan Chen; Guohui Shang; Baixue Liu; Mengjiao Xue; Youfei Lang; Guiling Zhou; Yichen Dong; Fengyan Zhang; Xuyan Peng; Yanzhong Hu

doi:10.1016/j.jbc.2024.108126

HSP90 stabilizes visual cycle retinol dehydrogenase 5 in the endoplasmic reticulum by inhibiting its degradation during autophagy

J Biol Chem. 2024 Dec 24:108126. doi: 10.1016/j.jbc.2024.108126. Online ahead of print.

Authors

Affiliations

¹ The Laboratory of Ophthalmology and Vision Science, Department of Ophthalmology, The Joint National Laboratory of Antibody Drug Engineering, Henan Province Engineering Research Center of Fundus Disease and Ocular Trauma Prevention and Treatment, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
² The Laboratory of Ophthalmology and Vision Science, Department of Ophthalmology, The Joint National Laboratory of Antibody Drug Engineering, Henan Province Engineering Research Center of Fundus Disease and Ocular Trauma Prevention and Treatment, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China; Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China.
³ Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Zhengzhou University, Henan, China.
⁴ The Laboratory of Ophthalmology and Vision Science, Department of Ophthalmology, The Joint National Laboratory of Antibody Drug Engineering, Henan Province Engineering Research Center of Fundus Disease and Ocular Trauma Prevention and Treatment, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China. Electronic address: xuyanpeng331@163.com.
⁵ The Laboratory of Ophthalmology and Vision Science, Department of Ophthalmology, The Joint National Laboratory of Antibody Drug Engineering, Henan Province Engineering Research Center of Fundus Disease and Ocular Trauma Prevention and Treatment, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China; Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, Zhengzhou, China; Kaifeng Key Lab for Cataracts and Myopia, Kaifeng Central Hospital, Kaifeng, China; Eye Institute, Henan Academy of Innovations in Medical Science, Zhengzhou, China. Electronic address: hyz@henu.edu.cn.

PMID: 39725039
DOI: 10.1016/j.jbc.2024.108126

Abstract

Genetic mutations in retinol dehydrogenase 5 (RDH5), a rate-limiting enzyme of the visual cycle, is associated with nyctalopia, AMD and stationary congenital fundus albipunctatus (FA). A majority of these mutations impair RDH5 protein expression and intracellular localization. However, the regulatory mechanisms underlying RDH5 metabolism remain unclear. Here, we find that RDH5 undergoes degradation via the autophagy-lysosomal pathway, and its stability is regulated by interacting with HSP90. Deletion of HSP90α or HSP90β by CRISPR-Cas9 or inhibition of HSP90 activity by IPI-504 down-regulates RDH5 protein level, but not its mRNA expression, and this downregulation is restored by autophagic inhibitors (3-MA, CQ and Baf-A1) and siRNA of ATG5 or ATG7, but not by the proteasome inhibitor MG132. RDH5 can physically interact with SQSTM1/P62, and this interaction is enhanced in HSP90-deficient cells as well as in CQ-treated cells. Knocking down SQSTM1/P62 by siRNA induces RDH5 protein accumulation. Moreover, HSP90, RDH5 and Calnexin form a complex through intermolecular interactions. Deficiency of HSP90α or HSP90β dissociates RDH5 from Calnexin, and increases RDH5 translocation from the endoplasmic reticulum (ER) to the cytosol. Taken together, we propose that dysfunction of HSP90 leads to RDH5 release from Calnexin in the ER into the cytosol, where it binds to the adaptor SQSTM1/P62 for degradation in the autolysosome. RDH5 is a novel client candidate of HSP90. The downregulation of RDH5 may be responsible for the nyctalopia side effect noted in cancer patients receiving HSP90 inhibitor treatment currently in the clinical trial.

Keywords: autophagy and endoplasmic reticulum; calnexin; heat shock protein 90; retinol dehydrogenase 5; visual cycle.