Melatonin induces autophagy via an mTOR-dependent pathway and enhances clearance of mutant-TGFBIp
Melatonin induces autophagy via an mTOR-dependent pathway and enhances clearance of mutant-TGFBIp
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DOI：
10.1111/jpi.12039
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发表时间：
2013-05-01
影响因子：
10.3
通讯作者：
Kim, Eung Kweon
中科院分区：
文献类型：
--
作者：
Choi, Seung-Il;Kim, Kyu Seo;Kim, Eung Kweon
颗粒状角膜营养不良2型（GCD 2）的标志是角膜中突变型转化生长因子（TGF-β）诱导的蛋白（TGF β 1 β）的存款。我们最近已经表明，在GCD 2角膜成纤维细胞中，通过受损的自噬通量，muplant-TGF β 1 β的自噬降解延迟。我们假设褪黑激素可以特异性地诱导自噬，从而消除GCD角膜成纤维细胞中的mu-TGF β 1 β。我们的研究结果表明，褪黑激素通过哺乳动物雷帕霉素靶蛋白（mTOR）依赖性途径激活野生型（WT）和GCD 2纯合型（HO）角膜成纤维细胞系中的自噬。褪黑激素治疗还导致beclin 1水平的增加，beclin 1参与自噬体的形成和成熟。此外，褪黑激素显着减少的量的突变型和WT-TGF β 1 β。用褪黑激素处理抵消了巴弗洛霉素A（自噬通量的有效抑制剂）的自噬抑制作用（1），表明褪黑激素增强自噬的激活并增加TGF β 1 β的降解。褪黑激素和雷帕霉素（一种自噬诱导剂）的联合治疗与单独使用任何一种药物治疗相比，对MUF-TGF β 1 β清除率有相加作用。用选择性褪黑激素受体拮抗剂luzindole治疗不能阻断褪黑激素诱导的自噬。鉴于其激活自噬的能力，褪黑激素是GCD 2的潜在治疗剂。
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.