Role of the ribosomal quality control machinery in nucleocytoplasmic translocation of polyQ-expanded huntingtin exon-1

Biochem Biophys Res Commun. 2017 Nov 4;493(1):708-717. doi: 10.1016/j.bbrc.2017.08.126. Epub 2017 Aug 30.

Abstract

The subcellular localization of polyQ-expanded huntingtin exon1 (Httex1) modulates polyQ toxicity in models of Huntington's disease. Using genome-wide screens in a yeast model system, we report that the ribosome quality control (RQC) machinery, recently implicated in neurodegeneration, is a key determinant for the nucleocytoplasmic distribution of Httex1-103Q. Deletion of the RQC genes, LTN1 or RQC1, caused the accumulation of Httex1-103Q in the nucleus through a process that required the CAT-tail tagging activity of Rqc2 and transport via the nuclear pore complex. We provide evidence that nuclear accumulation of Httex1-103Q enhances its cytotoxicity, suggesting that the RQC machinery plays an important role in protecting cells against the adverse effects of polyQ expansion proteins.

Keywords: Huntington's disease; Nucleocytoplasmic translocation; PolyQ protein; RQC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Cell Nucleus / metabolism*
  • Exons / genetics*
  • Humans
  • Huntingtin Protein / genetics*
  • Huntingtin Protein / metabolism*
  • Nucleocytoplasmic Transport Proteins / genetics
  • Nucleocytoplasmic Transport Proteins / metabolism
  • Peptides / genetics*
  • Peptides / metabolism*
  • Protein Binding
  • Ribosomes / metabolism*

Substances

  • Huntingtin Protein
  • Nucleocytoplasmic Transport Proteins
  • Peptides
  • polyglutamine