miR-376b controls starvation and mTOR inhibition-related autophagy by targeting ATG4C and BECN1
miR-376b controls starvation and mTOR inhibition-related autophagy by targeting ATG4C and BECN1
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DOI：
10.4161/auto.8.2.18351
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发表时间：
2012-02-01
期刊：
影响因子：
13.3
通讯作者：
Gozuacik, Devrim
中科院分区：
文献类型：
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作者：
Korkmaz, Gozde;le Sage, Carlos;Gozuacik, Devrim
自噬是细胞内长寿命蛋白质和细胞器降解的主要途径。它帮助细胞在一系列压力条件下生存，包括饥饿，生长因子剥夺和错误折叠的蛋白质积累。此外，自噬异常在包括癌症和神经退行性疾病在内的主要健康问题中发挥作用。然而，控制自噬活性的机制尚未完全了解。hsa-miR-376 b（miR-376 b）是一种新的调节自噬的microRNA（miRNA）。我们发现miR-376 b表达减弱了MCF-7和Huh-7细胞中饥饿和雷帕霉素诱导的自噬。我们发现自噬蛋白ATG 4C和BECN 1（Beclin 1）是miR-376 b的细胞靶点。事实上，在miRNA过表达时，ATG 4C和BECN 1的mRNA和蛋白水平均降低。miR-376 b靶序列存在于ATG 4C和BECN 1 mRNA的3' UTR中，并且突变的引入消除了它们的miR-376 b响应性。Antagomir介导的内源性miR-376 b失活导致ATG 4C和BECN 1水平升高。因此，miR-376 b通过直接调节两种关键自噬蛋白ATG 4C和BECN 1的细胞内水平来控制自噬。
Macroautophagy (autophagy) is the major intracellular degradation pathway for long-lived proteins and organelles. It helps the cell to survive a spectrum of stressful conditions including starvation, growth factor deprivation and misfolded protein accumulation. Moreover, abnormalities of autophagy play a role in major health problems including cancer and neurodegenerative diseases. Yet, mechanisms controlling autophagic activity are not fully understood. Here, we describe hsa-miR-376b (miR-376b) as a new microRNA (miRNA) regulating autophagy. We showed that miR-376b expression attenuated starvation-and rapamycin-induced autophagy in MCF-7 and Huh-7 cells. We discovered autophagy proteins ATG4C and BECN1 (Beclin 1) as cellular targets of miR-376b. Indeed, upon miRNA overexpression, both mRNA and protein levels of ATG4C and BECN1 were decreased. miR-376b target sequences were present in the 3' UTR of ATG4C and BECN1 mRNAs and introduction of mutations abolished their miR-376b responsiveness. Antagomir-mediated inactivation of the endogenous miR-376b led to an increase in ATG4C and BECN1 levels. Therefore, miR-376b controls autophagy by directly regulating intracellular levels of two key autophagy proteins, ATG4C and BECN1.