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

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 fibrobla...

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Bibliographic Details
Published in:Journal of pineal research 2013-05, Vol.54 (4), p.361-372
Main Authors: Choi, Seung-Il, Kim, Kyu Seo, Oh, Jun-Young, Jin, Jun-Yup, Lee, Ga-Hyun, Kim, Eung Kweon
Format: Article
Language:English
Subjects:
Animals
autophagy
Autophagy - drug effects
Base Sequence
Blotting, Western
Cells, Cultured
DNA Primers
granular corneal dystrophy type 2
Humans
LC3
melatonin
Melatonin - pharmacology
Microscopy, Electron, Transmission
mTOR
TGFBIp
TOR Serine-Threonine Kinases - metabolism
Transforming Growth Factor beta1 - metabolism
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Summary: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.
ISSN:0742-3098
1600-079X
DOI:10.1111/jpi.12039