SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation

Cell Rep. 2013 Jul 25;4(2):362-75. doi: 10.1016/j.celrep.2013.06.034. Epub 2013 Jul 18.

Abstract

A key feature in Huntington disease (HD) is the accumulation of mutant Huntingtin (HTT) protein, which may be regulated by posttranslational modifications. Here, we define the primary sites of SUMO modification in the amino-terminal domain of HTT, show modification downstream of this domain, and demonstrate that HTT is modified by the stress-inducible SUMO-2. A systematic study of E3 SUMO ligases demonstrates that PIAS1 is an E3 SUMO ligase for both HTT SUMO-1 and SUMO-2 modification and that reduction of dPIAS in a mutant HTT Drosophila model is protective. SUMO-2 modification regulates accumulation of insoluble HTT in HeLa cells in a manner that mimics proteasome inhibition and can be modulated by overexpression and acute knockdown of PIAS1. Finally, the accumulation of SUMO-2-modified proteins in the insoluble fraction of HD postmortem striata implicates SUMO-2 modification in the age-related pathogenic accumulation of mutant HTT and other cellular proteins that occurs during HD progression.

Publication types

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

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amino Acid Sequence
  • Animals
  • Catalytic Domain
  • Drosophila
  • Female
  • HeLa Cells
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Molecular Sequence Data
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Protein Inhibitors of Activated STAT / genetics
  • Protein Inhibitors of Activated STAT / metabolism*
  • Protein Processing, Post-Translational
  • Small Ubiquitin-Related Modifier Proteins / genetics
  • Small Ubiquitin-Related Modifier Proteins / metabolism*
  • Transfection
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • PIAS1 protein, human
  • Protein Inhibitors of Activated STAT
  • SUMO2 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • Ubiquitin-Protein Ligases