Rhes, a striatal-selective protein implicated in Huntington disease, binds beclin-1 and activates autophagy

J Biol Chem. 2014 Feb 7;289(6):3547-54. doi: 10.1074/jbc.M113.536912. Epub 2013 Dec 9.

Abstract

The protein mutated in Huntington disease (HD), mutant huntingtin (mHtt), is expressed throughout the brain and body. However, the pathology of HD is 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 of HD may reflect the striatal-selective expression and changes in autophagic activity of Rhes.

Keywords: Autophagy; Bcl-2; Beclin-1; Huntington Disease; Neurodegenerative Diseases; Rhes; mTOR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Autophagy*
  • Beclin-1
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • Gene Deletion
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mitogen-Activated Protein Kinase 8
  • PC12 Cells
  • Protein Binding
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • Becn1 protein, mouse
  • Becn1 protein, rat
  • Membrane Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • MTOR protein, human
  • mTOR protein, mouse
  • mTOR protein, rat
  • TOR Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 8
  • GTP-Binding Proteins
  • RASD2 protein, human
  • Rasd2 protein, mouse
  • Rasd2 protein, rat