title: HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis.
abstract: Huntington disease (HD) is caused by polyglutamine [poly(Q)] expansion in the protein huntingtin (htt). Although the exact mechanism of disease progression remains to be elucidated, altered interactions of mutant htt with its protein partners could contribute to the disease. Using the yeast two-hybrid system, we have isolated a novel htt interacting protein, HIP14. HIP14's interaction with htt is inversely correlated to the poly(Q) length in htt. mRNAs of 9 and 6 bp are transcribed from the HIP14 gene, with the 6 kb transcript being predominantly expressed in the brain. HIP14 protein is enriched in the brain, shows partial co-localization with htt in the striatum, and is found in medium spiny projection neurons, the subset of neurons affected in HD. HIP14 localizes to the Golgi, and to vesicles in the cytoplasm. The HIP14 protein has sequence similarity to Akr1p, a protein essential for endocytosis in Saccharomyces cerevisiae. Expression of human HIP14 results in rescue of the temperature-sensitive lethality in akr1 Delta yeast cells and, furthermore, restores their defect in endocytosis, demonstrating a role for HIP14 in intracellular trafficking. Our findings suggest that decreased interaction between htt and HIP14 could contribute to the neuronal dysfunction in HD by perturbing normal intracellular transport pathways in neurons.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Roshni R
authors.initials: RR
authors.lastname: Singaraja
authors.forename: Shinji
authors.initials: S
authors.lastname: Hadano
authors.forename: Martina
authors.initials: M
authors.lastname: Metzler
authors.forename: Scott
authors.initials: S
authors.lastname: Givan
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Wellington
authors.forename: Simon
authors.initials: S
authors.lastname: Warby
authors.forename: Anat
authors.initials: A
authors.lastname: Yanai
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Gutekunst
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
authors.forename: Hong
authors.initials: H
authors.lastname: Yi
authors.forename: Keith
authors.initials: K
authors.lastname: Fichter
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.forename: Krista
authors.initials: K
authors.lastname: McCutcheon
authors.forename: Vikramjit
authors.initials: V
authors.lastname: Chopra
authors.forename: Jennifer
authors.initials: J
authors.lastname: Michel
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hersch
authors.forename: Joh-E
authors.initials: JE
authors.lastname: Ikeda
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017487:Ankyrins / Q000737:chemistry / Q000378:metabolism; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D003001:Cloning, Molecular; D004705:Endocytosis / Q000502:physiology*; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D011817:Rabbits; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion; D020798:Two-Hybrid System Techniques
chemical_list: C110202:ANK1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C491707:Ank1 protein, mouse; D017487:Ankyrins; D002352:Carrier Proteins; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D000217:Acyltransferases; C473038:ZDHHC17 protein, human; C569387:Zdhhc17 protein, mouse