Kim Yunha, Lee Junghee, Ryu Hoon
Center for Neuromedicine, Korea Institute of Science and Technology, Seoul 136-791, Korea.
VA Boston Healthcare System, Boston, MA 02130, USA; Boston University Alzheimer's Disease Center and Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
BMB Rep. 2015 Jul;48(7):371-2. doi: 10.5483/bmbrep.2015.48.7.121.
MicroRNAs (miRNAs) can regulate the expression of genes that are involved in multiple cellular pathways. However, their targets and mechanism of action associated with the autophagy pathway are not fully investigated yet. EWSR1 (EWS RNA-Binding Protein 1/Ewing Sarcoma Break Point Region 1) gene encodes a RNA/DNA binding protein that is ubiquitously expressed and plays roles in numerous cellular processes. Recently, our group has shown that EWSR1 deficiency leads to developmental failure and accelerated senescence via processing of miRNAs, but its role in the regulation of autophagy remains elusive. In this context, we further investigated and found that EWSR1 deficiency triggers the activation of the DROSHA-mediated microprocessor complex and increases the levels of miR125a and miR351, which directly target Uvrag. Interestingly, the miR125a- and miR351-targeted reduction of Uvrag led to the inhibition of autophagy in both ewsr1 knockout (KO) MEFs and ewsr1 KO mice. In summary, our study demonstrates that EWSR1 is associated with the posttranscriptional regulation of Uvrag via miRNA processing. The regulation of autophagy pathway in miRNAs-Uvrag-dependent manner provides a novel mechanism of EWSR1 deficiency-related cellular dysfunction.
微小RNA（miRNA）可调控参与多种细胞通路的基因表达。然而，它们与自噬通路相关的靶标及作用机制尚未得到充分研究。EWSR1（EWS RNA结合蛋白1/尤因肉瘤断点区域1）基因编码一种RNA/DNA结合蛋白，该蛋白广泛表达并在众多细胞过程中发挥作用。最近，我们团队发现EWSR1缺陷通过miRNA的加工导致发育失败和加速衰老，但其在自噬调控中的作用仍不清楚。在此背景下，我们进一步研究发现，EWSR1缺陷会触发DROSHA介导的微处理器复合物的激活，并增加直接靶向Uvrag的miR125a和miR351的水平。有趣的是，miR125a和miR351靶向降低Uvrag会导致ewsr1基因敲除（KO）的小鼠胚胎成纤维细胞（MEF）和ewsr1基因敲除小鼠的自噬受到抑制。总之，我们的研究表明EWSR1通过miRNA加工与Uvrag的转录后调控相关。以miRNAs-Uvrag依赖的方式调控自噬通路为EWSR1缺陷相关的细胞功能障碍提供了一种新机制。
