HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis

• Published in: Human molecular genetics 2002-11, Vol.11 (23), p.2815-2828
• Main Authors: Singaraja, Roshni R., Hadano, Shinji, Metzler, Martina, Givan, Scott, Wellington, Cheryl L., Warby, Simon, Yanai, Anat, Gutekunst, Claire-Anne, Leavitt, Blair R., Yi, Hong, Fichter, Keith, Gan, Lu, McCutcheon, Krista, Chopra, Vikramjit, Michel, Jennifer, Hersch, Steven M., Ikeda, Joh-E, Hayden, Michael R.
• Format: Article
• Language: English
• Subjects: Acyltransferases - genetics; Acyltransferases - metabolism; Adaptor Proteins, Signal Transducing; Animals; Ankyrins - chemistry; Ankyrins - metabolism; Biological and medical sciences; Blotting, Northern; Brain - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cells, Cultured; Chromosome Mapping; Chromosomes, Human, Pair 12 - genetics; Cloning, Molecular; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Endocytosis - physiology; Female; Humans; Huntingtin Protein; Huntington Disease - metabolism; Immunoenzyme Techniques; Medical sciences; Mice; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Neurons - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Peptides - genetics; Peptides - metabolism; Protein Transport; Rabbits; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Trinucleotide Repeat Expansion; Two-Hybrid System Techniques
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/11.23.2815

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 akr1Δ 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.