Chaperone Peptides of α-Crystallin Inhibit Epithelial Cell Apoptosis, Protein Insolubilization, and Opacification in Experimental Cataracts

alpha-Crystallin is a member of the small heat-shock protein (sHSP) family and consists of two subunits, alpha A and alpha B. Both alpha A-and alpha B-crystallin act as chaperones and anti-apoptotic proteins. Previous studies have identified the peptide (KFVIFLD)-K-70-VKHFSPEDLTVK88 in alpha A-crystallin and the peptide (DRFS)-D-73-VNLDVKHFSPEELKVK92 in alpha B-crystallin as mini-chaperones. In the human lens, lysine 70 (Lys(70)) of alpha A and Lys92 of alpha B (in the mini-chaperone sequences) are acetylated. In this study, we investigated the cellular effects of the unmodified and acetyl mini-chaperones. The alpha A-and alpha B-crystallin peptides inhibited stress-induced aggregation of four client proteins, and the alpha A-acetyl peptide was more effective than the native peptide against three of the client proteins. Both the acetyl and native crystallin peptides inhibited stress-induced apoptosis in two mammalian cell types, and this property was directly related to the inhibition of cytochrome c release from mitochondria and the activity of caspase-3 and -9. In organ-cultured rat lenses, the peptides inhibited calcimycin-induced epithelial cell apoptosis. Intraperitoneal injection of the peptides inhibited cataract development in selenite-treated rats, which was accompanied by inhibition of oxidative stress, protein insolubilization, and caspase activity in the lens. These inhibitory effects were more pronounced for acetyl peptides than native peptides. A scrambled alpha A-crystallin peptide produced no such effects. The results suggest that the alpha-crystallin chaperone peptides could be used as therapeutic agents to treat cataracts and diseases in which protein aggregation and apoptosis are contributing factors.