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Melatonin induces autophagy via an mTOR-dependent pathway and enhances clearance of mutant-TGFBIp

Authors
 Seung-Il Choi ; Kyu Seo Kim ; Eung Kweon Kim ; Ga-Hyun Lee ; Jun-Yup Jin ; Jun-Young Oh 
Citation
 Journal of Pineal Research, Vol.54(4) : 361~372, 2013 
Journal Title
 Journal of Pineal Research 
ISSN
 0742-3098 
Issue Date
2013
Abstract
The hallmark of granular corneal dystrophy type 2 (GCD2) is the deposit of mutant transforming growth factor-β (TGF-β)-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 A1, 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.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/87090
DOI
10.1111/jpi.12039
Appears in Collections:
1. 연구논문 > 5. Research Institutes > Corneal Dystrophy Research Institute
1. 연구논문 > 1. College of Medicine > Dept. of Ophthalmology
1. 연구논문 > 1. College of Medicine > Yonsei Biomedical Research Center
1. 연구논문 > 1. College of Medicine > Dept. of Life Science
Yonsei Authors
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Link
 http://onlinelibrary.wiley.com/doi/10.1111/jpi.12039/abstract
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