Journal Article

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

Roshni R. Singaraja, Shinji Hadano, Martina Metzler, Scott Givan, Cheryl L. Wellington, Simon Warby, Anat Yanai, Claire-Anne Gutekunst, Blair R. Leavitt, Hong Yi, Keith Fichter, Lu Gan, Krista McCutcheon, Vikramjit Chopra, Jennifer Michel, Steven M. Hersch, Joh-E Ikeda and Michael R. Hayden

in Human Molecular Genetics

Volume 11, issue 23, pages 2815-2828
Published in print November 2002 | ISSN: 0964-6906
Published online November 2002 | e-ISSN: 1460-2083 | DOI:
HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis

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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.

Journal Article.  8137 words.  Illustrated.

Subjects: Genetics and Genomics

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