Kinase inhibitors modulate huntingtin cell localization and toxicity

Nat Chem Biol. 2011 May 29;7(7):453-60. doi: 10.1038/nchembio.582.

Abstract

Two serine residues within the first 17 amino acid residues of huntingtin (N17) are crucial for modulation of mutant huntingtin toxicity in cell and mouse genetic models of Huntington's disease. Here we show that the stress-dependent phosphorylation of huntingtin at Ser13 and Ser16 affects N17 conformation and targets full-length huntingtin to chromatin-dependent subregions of the nucleus, the mitotic spindle and cleavage furrow during cell division. Polyglutamine-expanded mutant huntingtin is hypophosphorylated in N17 in both homozygous and heterozygous cell contexts. By high-content screening in live cells, we identified kinase inhibitors that modulated N17 phosphorylation and hence huntingtin subcellular localization. N17 phosphorylation was reduced by casein kinase-2 inhibitors. Paradoxically, IKKβ kinase inhibition increased N17 phosphorylation, affecting huntingtin nuclear and subnuclear localization. These data indicate that huntingtin phosphorylation at Ser13 and Ser16 can be modulated by small-molecule drugs, which may have therapeutic potential in Huntington's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Casein Kinase II / antagonists & inhibitors*
  • Cell Line
  • Cell Nucleus / metabolism
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Endoplasmic Reticulum / metabolism
  • Fluorescent Antibody Technique
  • Huntingtin Protein
  • Huntington Disease / enzymology
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • I-kappa B Kinase / antagonists & inhibitors*
  • Mice
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Nuclear Proteins / genetics*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • Serine / genetics
  • Spindle Apparatus / metabolism
  • Transfection

Substances

  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Serine
  • Casein Kinase II
  • I-kappa B Kinase

Associated data

  • PubChem-Substance/121270650
  • PubChem-Substance/121270651
  • PubChem-Substance/121270652
  • PubChem-Substance/121270653
  • PubChem-Substance/121270654
  • PubChem-Substance/121270655
  • PubChem-Substance/121270656