Kim Yunha, Kang Young-Sook, Lee Na-Young, Kim Ki Yoon, Hwang Yu Jin, Kim Hyun-Wook, Rhyu Im Joo, Her Song, Jung Min-Kyung, Kim Sun, Lee Chai-Jin, Ko Seyoon, Kowall Neil W, Lee Sean Bong, Lee Junghee, Ryu Hoon
a Laboratory for Neuronal Gene Regulation and Epigenetics; Center for NeuroMedicine; Korea Institute of Science and Technology ; Seoul , Korea.
Autophagy. 2015;11(5):796-811. doi: 10.1080/15548627.2015.1035503.
The EWSR1 (EWS RNA-binding protein 1/Ewing Sarcoma Break Point Region 1) gene encodes a RNA/DNA binding protein that is ubiquitously expressed and involved in various cellular processes. EWSR1 deficiency leads to impairment of development and accelerated senescence but the mechanism is not known. Herein, we found that EWSR1 modulates the Uvrag (UV radiation resistance associated) gene at the post-transcription level. Interestingly, EWSR1 deficiency led to the activation of the DROSHA-mediated microprocessor complex and increased the level of Mir125a and Mir351, which directly target Uvrag. Moreover, the Mir125a- and Mir351-mediated reduction of Uvrag was associated with the inhibition of autophagy that was confirmed in ewsr1 knockout (KO) MEFs and ewsr1 KO mice. Taken together, our data indicate that EWSR1 is involved in the post-transcriptional regulation of Uvrag via a miRNA-dependent pathway, resulting in the deregulation of autophagy inhibition. The mechanism of Uvrag and autophagy regulation by EWSR1 provides new insights into the role of EWSR1 deficiency-related cellular dysfunction.
EWSR1（EWS RNA结合蛋白1/尤文肉瘤断点区域1）基因编码一种RNA/DNA结合蛋白，该蛋白在全身广泛表达并参与各种细胞过程。EWSR1缺陷会导致发育受损和加速衰老，但其机制尚不清楚。在此，我们发现EWSR1在转录后水平调节Uvrag（紫外线辐射抗性相关）基因。有趣的是，EWSR1缺陷导致DROSHA介导的微处理器复合物激活，并增加了直接靶向Uvrag的Mir125a和Mir351的水平。此外，Mir125a和Mir351介导的Uvrag减少与自噬抑制有关，这在ewsr1基因敲除（KO）的小鼠胚胎成纤维细胞（MEFs）和ewsr1基因敲除小鼠中得到证实。综上所述，我们的数据表明EWSR1通过miRNA依赖的途径参与Uvrag的转录后调控，导致自噬抑制失调。EWSR1对Uvrag和自噬的调控机制为EWSR1缺陷相关细胞功能障碍的作用提供了新的见解。
