Rhes, a Striatal-selective Protein Implicated in Huntington Disease, Binds Beclin-1 and activates autophagy

Robert G. Mealer, Alexandra J. Murray, Neelam Shahani, Srinivasa Subramaniam, Solomon H. Snyder

Research output: Contribution to journalArticle

Abstract

Background: The striatal-specific protein Rhes is implicated in the selective pathology of HD. Results: Rhes binds Beclin-1 and activates autophagy, a lysosomal degradation pathway critical in aging and neurodegeneration. Conclusion: Rhes-induced autophagy occurs independent of mTOR and JNK-1 signaling and is inhibited by huntingtin. Significance: The restricted expression of Rhes and its effect on autophagy may explain the selective striatal pathology and delayed onset of HD. The protein mutated in Huntington disease (HD), mutant huntingtin (mHtt), is expressed throughout the brain and body. However, the pathology ofHDis characterized by early and dramatic destruction selectively of the striatum. We previously reported that the striatal-specific protein Rhes binds mHtt and enhances its cytotoxicity. Moreover, Rhes-deleted mice are dramatically protected from neurodegeneration and motor dysfunction in mouse models of HD. We now report a function of Rhes in autophagy, a lysosomal degradation pathway implicated in aging and HD neurodegeneration. In PC12 cells, deletion of endogenous Rhes decreases autophagy, whereas Rhes overexpression activates autophagy. These effects are independent of mTOR and opposite in the direction predicted by the known activation of mTOR by Rhes. Rhes robustly binds the autophagy regulator Beclin-1, decreasing its inhibitory interaction with Bcl-2 independent of JNK-1 signaling. Finally, co-expression of mHtt blocks Rhes-induced autophagy activation. Thus, the isolated pathology and delayed onset ofHDmay reflect the striatalselective expression and changes in autophagic activity of Rhes.

Original languageEnglish (US)
Pages (from-to)3547-3554
Number of pages8
JournalJournal of Biological Chemistry
Volume289
Issue number6
DOIs
StatePublished - Feb 7 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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