title: Uvrag targeting by Mir125a and Mir351 modulates autophagy associated with Ewsr1 deficiency.
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 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.
authors.affiliation: a Laboratory for Neuronal Gene Regulation and Epigenetics; Center for NeuroMedicine; Korea Institute of Science and Technology ; Seoul , Korea.
authors.forename: Yunha
authors.initials: Y
authors.lastname: Kim
authors.forename: Young-Sook
authors.initials: YS
authors.lastname: Kang
authors.forename: Na-Young
authors.initials: NY
authors.lastname: Lee
authors.forename: Ki Yoon
authors.initials: KY
authors.lastname: Kim
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Hwang
authors.forename: Hyun-Wook
authors.initials: HW
authors.lastname: Kim
authors.forename: Im Joo
authors.initials: IJ
authors.lastname: Rhyu
authors.forename: Song
authors.initials: S
authors.lastname: Her
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Jung
authors.forename: Sun
authors.initials: S
authors.lastname: Kim
authors.forename: Chai-Jin
authors.initials: CJ
authors.lastname: Lee
authors.forename: Seyoon
authors.initials: S
authors.lastname: Ko
authors.forename: Neil W
authors.initials: NW
authors.lastname: Kowall
authors.forename: Sean Bong
authors.initials: SB
authors.lastname: Lee
authors.forename: Junghee
authors.initials: J
authors.lastname: Lee
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D001483:Base Sequence; D002148:Calmodulin-Binding Proteins / Q000172:deficiency* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D002148:Calmodulin-Binding Proteins; C000605150:Ewsr1 protein, mouse; C580764:MIRN351 microRNA, 351; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C512859:UVRAG protein, mouse
keywords: AGO2, argonaute; ATG12, autophagy-related 12; ATG14, autophagy-related 14; ATG5, autophagy-related 5; Ant-Mir125a; Ant-Mir351; BECN1, Beclin 1; CNT-Ant, control antagomir; CQ, chloroquine; DGCR8, DiGeorge syndrome critical region gene 8; EWS, Ewing's Sarcoma; EWSR1; EWSR1, EWS RNA-binding protein 1/Ewing Sarcoma Break Point Region 1; Ewsr1+/+; Ewsr1 homozygous knockout; Ewsr1 wild type; ewsr1−/−; LAMP, lysosomal-associated membrane protein; MAP1LC3/LC3; MEF, mouse embryonic fibroblast; Mir125a; Mir125a-specific antagomir; Mir351; Mir351-specific antagomir; Pep.A, pepstatin A; RISC, catalytic component 2; RNA-seq, whole transcriptome sequencing; SQSTM1, sequestosome 1; UVRAG; UVRAG, UV radiation-resistance associated; autophagy; miRNA, microRNA; microtubule-associated protein 1 light chain 3; pri-miRNA, primary transcript miRNA; siRNA, small interfering RNA