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Autophagy, 06 May 2015, DOI:10.1080/15548627.2015.1035503 Uvrag targeting by Mir125a and Mir351 modulates autophagy associated with Ewsr1 deficiency

Abstract

Yunha Kim^a, Young-Sook Kang^b, Na-Young Lee^b, Ki Yoon Kim^a, Yu Jin Hwang^a, Hyun-Wook Kim^c, Im Joo Rhyu^c, Song Her^d, Min-Kyung Jung^a, Sun Kim^ef, Chai-Jin Lee^e, Seyoon Ko^f, Neil W. Kowall^gh, Sean Bong Leeⁱ, Junghee Lee^gh & Hoon Ryu^agh*

^a Laboratory for Neuronal Gene Regulation and Epigenetics, Center for NeuroMedicine, Korea Institute of Science and Technology, Seoul, South Korea

^b Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 140-742, South Korea

^c Department of Anatomy, College of medicine, Korea university, Seoul, South Korea

^d Bio-Imaging Center, Korea Basic Science Institute, Chuncheon, South Korea

^e Interdisciplinary Program in Bioinformatics and Computational Science & Technology

^f Department of Computer Science and Engineering, and Bioinformatics Institute, Seoul National University, Seoul, South Korea

^g Veteran's Affairs Boston Healthcare System, Boston, MA 02130, USA

^h Boston University Alzheimer's Disease Center and Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA

ⁱ Department of Pathology & Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA

^*To whom correspondence may be addressed.

Abstract

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 posttranscription 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 posttranscriptional 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.

논문정보

형식Research article
게재일2015년 05월 (BRIC 등록일 2015-05-14)
연구진국내(교신)+국외 연구진
분야 의약학 > 분자세포의학

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