title: Heat shock factor 4 regulates lens epithelial cell homeostasis by working with lysosome and anti-apoptosis pathways.
abstract: Activation of Heat shock factor 4-mediated heat shock response is closely associated with postnatal lens development. HSF4 controls the expression of small heat shock proteins (e.g. HSP25 and CRYAB) in lens epithelial cells. However, their roles in modulating lens epithelium homeostasis remain unclear. In this paper, we find that HSF4 is developmentally expressed in mouse lens epithelium and fiber tissue. HSF4 and alpha B-crystallin can selectively protect lens epithelial cells from cisplatin and H2O2 induced apoptosis by stabilizing mitochondrial membrane potential (ΔYm) and reducing ROS production. In addition, to our surprise, HSF4 is involved in upregulating lysosome activity. We found mLEC/HA-Hsf4 cells to have increased DLAD expression, lysosome acidity, cathepsin B activity, and degradation of plasmid DNA and GFP-LC3 protein when compared to mLEC/Hsf4-/- cells. Knocking down Cryab from mLEC/HA-Hsf4 cells inhibits HSF4-mediated lysosome acidification, while overexpression of CRYAB can upregulate cathepsin B activity in mLEC/Hsf4-/- cells. CRAYAB can interact with ATP6V1/A the A subunit of the H+pump vacuolar ATPase, and is colocalized to lamp1 and lamp2 in the lysosome. Collectively, these results suggest that in addition to modulating anti-apoptosis, HSF4 is able to regulate lysosome activity by at least controlling alpha B-crystallin expression, shedding light on a novel molecular mechanism of HSF4 in regulating lens epithelial cell homeostasis.
authors: Henan International Union Laboratory of Antibody Medicine, Henan Engineering Lab of Antibody Medicine, Institute of Molecular and Cellular immunology, Department of Cell biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China.
authors: Xiukun
authors: X
authors: Cui
authors: Henan International Union Laboratory of Antibody Medicine, Henan Engineering Lab of Antibody Medicine, Institute of Molecular and Cellular immunology, Department of Cell biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China.
authors: Huiyuan
authors: H
authors: Liu
authors: Henan International Union Laboratory of Antibody Medicine, Henan Engineering Lab of Antibody Medicine, Institute of Molecular and Cellular immunology, Department of Cell biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China.
authors: Jing
authors: J
authors: Li
authors: Henan International Union Laboratory of Antibody Medicine, Henan Engineering Lab of Antibody Medicine, Institute of Molecular and Cellular immunology, Department of Cell biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China.
authors: Kangwen
authors: K
authors: Guo
authors: Henan International Union Laboratory of Antibody Medicine, Henan Engineering Lab of Antibody Medicine, Institute of Molecular and Cellular immunology, Department of Cell biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China.
authors: Wenxiu
authors: W
authors: Han
authors: Henan International Union Laboratory of Antibody Medicine, Henan Engineering Lab of Antibody Medicine, Institute of Molecular and Cellular immunology, Department of Cell biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China; Kaifeng Key Lab of Cataract and Myopia, Institute of Eye Diseases, Kaifeng Centre Hospital, Kaifeng, Henan, China.
authors: Yi
authors: Y
authors: Dong
authors: Henan International Union Laboratory of Antibody Medicine, Henan Engineering Lab of Antibody Medicine, Institute of Molecular and Cellular immunology, Department of Cell biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China; Kaifeng Key Lab of Cataract and Myopia, Institute of Eye Diseases, Kaifeng Centre Hospital, Kaifeng, Henan, China.
authors: Simin
authors: S
authors: Wan
authors: Henan International Union Laboratory of Antibody Medicine, Henan Engineering Lab of Antibody Medicine, Institute of Molecular and Cellular immunology, Department of Cell biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China; Kaifeng Key Lab of Cataract and Myopia, Institute of Eye Diseases, Kaifeng Centre Hospital, Kaifeng, Henan, China.
authors: Xuance
authors: X
authors: Wang
authors: Henan International Union Laboratory of Antibody Medicine, Henan Engineering Lab of Antibody Medicine, Institute of Molecular and Cellular immunology, Department of Cell biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China.
authors: Panpan
authors: P
authors: Jia
authors: Henan International Union Laboratory of Antibody Medicine, Henan Engineering Lab of Antibody Medicine, Institute of Molecular and Cellular immunology, Department of Cell biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China.
authors: Shulian
authors: S
authors: Li
authors: Henan International Union Laboratory of Antibody Medicine, Henan Engineering Lab of Antibody Medicine, Institute of Molecular and Cellular immunology, Department of Cell biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China.
authors: Yuanfang
authors: Y
authors: Ma
authors: Henan International Union Laboratory of Antibody Medicine, Henan Engineering Lab of Antibody Medicine, Institute of Molecular and Cellular immunology, Department of Cell biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China.
authors: Jun
authors: J
authors: Zhang
authors: Kaifeng Key Lab of Cataract and Myopia, Institute of Eye Diseases, Kaifeng Centre Hospital, Kaifeng, Henan, China.
authors: Hongmei
authors: H
authors: Mu
authors: Henan International Union Laboratory of Antibody Medicine, Henan Engineering Lab of Antibody Medicine, Institute of Molecular and Cellular immunology, Department of Cell biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, China; Kaifeng Key Lab of Cataract and Myopia, Institute of Eye Diseases, Kaifeng Centre Hospital, Kaifeng, Henan, China. Electronic address: hyz@henu.edu.cn.
authors: Yanzhong
authors: Y
authors: Hu
mesh_terms: D000818:Animals; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D057809:HEK293 Cells; D000076249:Heat Shock Transcription Factors; D006706:Homeostasis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007908:Lens, Crystalline / Q000166:cytology*; D008247:Lysosomes / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation; D038203:alpha-Crystallin B Chain / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C484462:Hsf4 protein, mouse; D014157:Transcription Factors; D038203:alpha-Crystallin B Chain
keywords: Alpha B-crystallin; Apoptosis; HSF4; Lysosome; Mitochondria