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Uvrag targeting by Mir125a and Mir351 modulates autophagy associated with Ewsr1 deficiency

Yunha Kim1, Young-Sook Kang, Na-Young Lee

  • 1a Laboratory for Neuronal Gene Regulation and Epigenetics; Center for NeuroMedicine; Korea Institute of Science and Technology ; Seoul , Korea.

Autophagy
|May 7, 2015
PubMed

Insights

EWSR1 protein regulates UV radiation resistance associated gene (Uvrag) post-transcriptionally. EWSR1 deficiency disrupts this, increasing microRNAs that target Uvrag, leading to autophagy inhibition and cellular dysfunction.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • The EWSR1 (EWS RNA-binding protein 1/Ewing Sarcoma Break Point Region 1) gene is crucial for cellular processes.
  • EWSR1 deficiency causes developmental impairment and accelerated senescence, but the underlying mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the mechanism by which EWSR1 deficiency leads to cellular dysfunction.
  • To investigate the role of EWSR1 in the post-transcriptional regulation of the Uvrag gene and its impact on autophagy.

Main Methods:

  • Investigated EWSR1's modulation of the Uvrag gene at the post-transcriptional level.
  • Analyzed the activation of the DROSHA-mediated microprocessor complex and microRNA levels (Mir125a, Mir351) in EWSR1-deficient cells.
  • Confirmed the impact of microRNA-mediated Uvrag reduction on autophagy using EWSR1 knockout MEFs and mice.

Main Results:

  • EWSR1 deficiency activates the DROSHA-mediated microprocessor complex, increasing Mir125a and Mir351 levels.
  • These microRNAs directly target and reduce Uvrag levels.
  • Reduced Uvrag levels due to microRNAs inhibit autophagy, as observed in EWSR1 knockout models.

Conclusions:

  • EWSR1 regulates Uvrag post-transcriptionally through a microRNA-dependent pathway.
  • This pathway is critical for maintaining autophagy.
  • Dysregulation of Uvrag and autophagy by EWSR1 deficiency contributes to cellular dysfunction.
Keywords:
AGO2, argonauteATG12, autophagy-related 12ATG14, autophagy-related 14ATG5, autophagy-related 5Ant-Mir125aAnt-Mir351BECN1, Beclin 1CNT-Ant, control antagomirCQ, chloroquineDGCR8, DiGeorge syndrome critical region gene 8EWS, Ewing's SarcomaEWSR1EWSR1, EWS RNA-binding protein 1/Ewing Sarcoma Break Point Region 1; Ewsr1+/+Ewsr1 homozygous knockoutEwsr1 wild type; ewsr1−/−LAMP, lysosomal-associated membrane protein; MAP1LC3/LC3MEF, mouse embryonic fibroblastMir125aMir125a-specific antagomirMir351Mir351-specific antagomirPep.A, pepstatin ARISC, catalytic component 2RNA-seq, whole transcriptome sequencingSQSTM1, sequestosome 1UVRAGUVRAG, UV radiation-resistance associatedautophagymiRNA, microRNAmicrotubule-associated protein 1 light chain 3pri-miRNA, primary transcript miRNAsiRNA, small interfering RNA

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