MicroRNA-29 enhances autophagy and cleanses exogenous mutant αB-crystallin in retinal pigment epithelial cells
MicroRNA-29 enhances autophagy and cleanses exogenous mutant αB-crystallin in retinal pigment epithelial cells
复制标题
MicroRNA-29增强视网膜色素上皮细胞自噬并清除外源突变体αB-晶状体蛋白
DOI：
10.1016/j.yexcr.2018.11.028
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发表时间：
2019-01-01
影响因子：
3.7
通讯作者：
Wu, Shengzhou
中科院分区：
文献类型：
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作者：
Cai, Jingjing;Zhang, He;Wu, Shengzhou
视网膜色素上皮细胞（RPE）是视网膜外层的色素细胞层，经常暴露于光氧化应激。自噬通过清除氧化蛋白加合物、蛋白质聚集体和受损的线粒体来缓解应激。我们先前发现，在渗出性年龄相关性黄斑变性（AMD）模型中，miR-29在脉络膜/RPE组织中下调，表明miR-29缺乏可能有助于自噬抑制和AMD进展。在这里，我们想测试在RPE中过表达miR-29是否可以增强自噬，从而促进玻璃疣成分的去除。事实上，RPE中miR-29的过表达增加了自噬，通过降低的p62蛋白水平、增加的微管相关蛋白轻链（LC 3-II）的脂质形式和升高的自噬通量来评估。此外，miR-29的过表达减轻了突变体α B-晶状体蛋白（R120 G）蛋白聚集体的形成。在探索其机制时，我们证明了miR-29通过靶向其信使RNA的3 '-UTR转录后抑制LAMPTOR 1/p18。miR-29过表达和LAMPTOR 1/p18的敲低导致mTORC 1向溶酶体的募集有限并抑制mTORC 1活性。总之，miR-29增强自噬，这有助于去除蛋白质聚集体。这些发现揭示了miR-29的新作用，其具有作为挽救眼部疾病中的RPE变性的治疗策略的潜力。
Retinal pigment epithelial cells (RPEs), a pigmented cell layer in the outer retina, are constantly exposed to photo-oxidative stress. Autophagy relieves the stress by removing oxidative protein adducts, protein aggregates, and damaged mitochondria. We previously found that miR-29 is downregulated in choroid/RPE tissue in a model of exudative age-related macular degeneration (AMD), suggesting that miR-29 deficiency may contribute to autophagy inhibition and AMD progression. Here we wanted to test whether overexpression of miR-29 in RPEs could enhance autophagy, thereby facilitating removal of drusen components. Indeed, overexpression of miR-29 in the RPEs increased autophagy, assessed by decreased protein levels of p62, increased lipid form of microtubule-associated protein light chain (LC3-II), and elevated autophagy flux. Furthermore, overexpression of miR-29 mitigated the formation of mutant alpha B-crystallin (R120G) protein aggregates. In probing the mechanism, we demonstrated that miR-29 post-transcriptionally repressed LAMPTOR1/p18 via targeting its 3'-UTRs of messenger RNA. MiR-29 overexpression and knockdown of LAMPTOR1/p18 led to limited mTORC1 recruitment to lysosomes and inhibition of mTORC1 activity. Altogether, miR-29 enhances autophagy which aids in removal of protein aggregates. These findings reveal a novel role of miR-29, which has the potential of being a therapeutic strategy for rescuing RPE degeneration in ocular disorders.