title: Kinase inhibitors modulate huntingtin cell localization and toxicity.
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.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Randy Singh
authors.initials: RS
authors.lastname: Atwal
authors.forename: Carly R
authors.initials: CR
authors.lastname: Desmond
authors.forename: Nicholas
authors.initials: N
authors.lastname: Caron
authors.forename: Tamara
authors.initials: T
authors.lastname: Maiuri
authors.forename: Jianrun
authors.initials: J
authors.lastname: Xia
authors.forename: Simonetta
authors.initials: S
authors.lastname: Sipione
authors.forename: Ray
authors.initials: R
authors.lastname: Truant
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012694:Serine / Q000235:genetics; D008941:Spindle Apparatus / Q000378:metabolism; D014162:Transfection
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D012694:Serine; D047390:Casein Kinase II; D051550:I-kappa B Kinase