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Human Molecular Genetics, 2002, Vol. 11, No. 23 2815-2828
© 2002 Oxford University Press

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

Roshni R. Singaraja1, Shinji Hadano1,2, Martina Metzler1, Scott Givan1, Cheryl L. Wellington1, Simon Warby1, Anat Yanai1, Claire-Anne Gutekunst3, Blair R. Leavitt1, Hong Yi3, Keith Fichter1, Lu Gan1, Krista McCutcheon1, Vikramjit Chopra1, Jennifer Michel1, Steven M. Hersch3, Joh-E Ikeda2,4 and Michael R. Hayden1,*

1Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4, 2NeuroGenes, International Cooperative Research Project, Japan Science and Technology Corporation, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan, 3Emory University School of Medicine, Atlanta, GA 30322, USA and 4Department of Molecular Neuroscience, Molecular Medicine Research Center, The Institute of Medical Sciences, Tokai University, Isehara, Kanagawa 259-1193, Japan

Received June 4, 2002; Accepted August 26, 2002

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.

* To whom correspondence should be addressed at: Centre for Molecular Medicine and Therapeutics, University of British Columbia, 980 West 28th Avenue, Vancouver, Canada BC V5Z 4H4. Tel: +1 6048753535; Fax:+1 6048753819; Email: mrh{at}cmmt.ubc.ca


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