期刊
JOURNAL OF PINEAL RESEARCH
卷 54, 期 4, 页码 361-372出版社
WILEY-BLACKWELL
DOI: 10.1111/jpi.12039
关键词
autophagy; granular corneal dystrophy type 2; LC3; melatonin; (mTOR); TGFBIp
资金
- Converging Research Center Program through the National Research Foundation of Korea (NRF)
- Ministry of Education, Science, and Technology (MEST) [2012K001354, 2011-0028699]
- Midcareer Researcher Program grant through the NRF
The hallmark of granular corneal dystrophy type 2 (GCD2) is the deposit of mutant transforming growth factor- (TGF-)-induced protein (TGFBIp) in the cornea. We have recently shown that there is a delay in autophagic degradation of mutant-TGFBIp via impaired autophagic flux in GCD2 corneal fibroblasts. We hypothesized that melatonin can specifically induce autophagy and consequently eliminate mutant-TGFBIp in GCD corneal fibroblasts. Our results show that melatonin activates autophagy in both wild-type (WT) and GCD2-homozygous (HO) corneal fibroblast cell lines via the mammalian target of rapamycin (mTOR)-dependent pathway. Melatonin treatment also led to increased levels of beclin 1, which is involved in autophagosome formation and maturation. Furthermore, melatonin significantly reduced the amounts of mutant- and WT-TGFBIp. Treatment with melatonin counteracted the autophagy-inhibitory effects of bafilomycin A(1), a potent inhibitor of autophagic flux, demonstrating that melatonin enhances activation of autophagy and increases degradation of TGFBIp. Cotreatment with melatonin and rapamycin, an autophagy inducer, had an additive effect on mutant-TGFBIp clearance compared to treatment with either drug alone. Treatment with the selective melatonin receptor antagonist luzindole did not block melatonin-induced autophagy. Given its ability to activate autophagy, melatonin is a potential therapeutic agent for GCD2.
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