Heat shock factor 4 regulates lens epithelial cell homeostasis by working with lysosome and anti-apoptosis pathways

• DOI: 10.1016/j.biocel.2016.08.022
• Publication Date: 2016-09-02T23:26:09Z
• Authors: Xiukun Cui; Huiyuan Liu; Jing Li; Kangwen Guo; Wenxiu Han; Yi Dong; Simin Wan; Xuance Wang; Panpan Jia; Shulian Li; Yuanfang Ma; Jun Zhang; Hongmei Mu; Yanzhong Hu
• Keywords: 0303 health sciences; 610; alpha-Crystallin B Chain; Apoptosis; Epithelial Cells; Hydrogen-Ion Concentration; Mitochondria; Up-Regulation; DNA-Binding Proteins; Mice; 03 medical and health sciences; HEK293 Cells; Heat Shock Transcription Factors; Lens, Crystalline; Animals; Homeostasis; Humans; Lysosomes; Transcription Factors

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.