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HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain

Nature Genetics volume 16, pages 44–53 (1997)Cite this article

Abstract

Huntington disease (HD) is associated with the expansion of a polyglutamine tract, greater than 35 repeats, in the HD gene product, huntingtin. Here we describe a novel huntingtin interacting protein, HIP1, which co-localizes with huntingtin and shares sequence homology and biochemical characteristics with Sla2p, a protein essential for function of the cytoskeleton in Saccharomyces cerevisiae. The huntingtin–HIP1 interaction is restricted to the brain and is inversely correlated to the polyglutamine length in huntingtin. This provides the first molecular link between huntingtin and the neuronal cytoskeleton and suggests that, in HD, loss of normal huntingtin–HIP1 interaction may contribute to a defect in membrane-cytoskeletal integrity in the brain.

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References

  1. Ross, C.A. When more is less: Pathogenesis of glutamine repeat neurodegenerative diseases. Neuron 15, 493–496 (1995).

    Article  CAS  Google Scholar 

  2. Zoghbi, H.Y. The expanding world of ataxins. Nature Genet. 14, 237–239 (1996).

    Article  CAS  Google Scholar 

  3. Hayden, M.R. Huntington's chorea. 59–75, (Springer-Verlag, London, Berlin, 1981).

    Chapter  Google Scholar 

  4. Harper, P.S., Huntington's chorea. 31–72 (W.B. Saunders, London, 1991).

  5. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72, 971–983 (1993).

    Article  Google Scholar 

  6. Kremer, H.P.H. et al. A worldwide study of the Huntington's disease mutation: The sensitivity and specificity of measuring CAG repeats. New. Engl. J. Med. 330, 1401–1406 (1994).

    Article  CAS  Google Scholar 

  7. Andrew, S.E. et al. The relationship between trinucleotide repeat (CAG) length and clinical features of Huntington disease. Nature Genet. 4, 398–403 (1993).

    Article  CAS  Google Scholar 

  8. Duyao, M. et al. Trinucleotide repeat length instability in Huntington disease. Nature Genet. 4, 387–392 (1993).

    Article  CAS  Google Scholar 

  9. Snell, R.G. et al. Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nature Genet. 4, 393–397 (1993).

    Article  CAS  Google Scholar 

  10. Lin, B.-Y. et al. Differential 3′ polyadenylation of the Huntington disease gene results in two mRNA species with variable tissue expression. Hum. Mol. Genet. 2, 1541–1545 (1993).

    Article  CAS  Google Scholar 

  11. Schilling, G. et al. Expression of the Huntington's disease (IT15) protein product in HD patients. Hum. Mol. Genet. 5, 1365–1371 (1995).

    Article  Google Scholar 

  12. Sharp, A. et al. Widespread expression of Huntington's disease gene (IT-15) protein product. Neuron 14, 1065–1074 (1995).

    Article  CAS  Google Scholar 

  13. Aronin, N. et al. CAG Expansion affects the expression of mutant huntingtin in the huntington's disease brain. Neuron 15, 1193–1201 (1995).

    Article  CAS  Google Scholar 

  14. Vonsattel, J.P. et al. Neuropathological classification of Huntington's disease. J. Neuropathol. Exp. Neurol. 44, 559–577 (1985).

    Article  CAS  Google Scholar 

  15. Servadio, A. et al. Expression analysis of the ataxin-1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals. Nature Genet. 10, 94–98 (1995).

    Article  CAS  Google Scholar 

  16. DiFiglia, M. et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 14, 1075–1141 (1995).

    Article  CAS  Google Scholar 

  17. Telenius, H. et al. Molecular analysis of juvenile Huntington disease: the major influence on (CAG)n repeat length is the sex of the affected parent. Hum. Mol. Genet. 2, 1535–1540 (1993).

    Article  CAS  Google Scholar 

  18. Chien, C.-T., Bartel, P.L., Sternglanz, R. & Fields, S. The two-hybrid system: A method to identify and clone genes for proteins that interact with a protein of interest. Proc. Natl. Acad. Sci. USA. 88, 9578–9582 (1991).

    Article  CAS  Google Scholar 

  19. Fields, S. & Song, O.-K. A novel genetic system to detect protein-protein interacts. Nature 340, 245–246 (1993).

    Article  Google Scholar 

  20. Holtzman, D.A., Yang, S. & Drubin, D.G. Synthetic-lethal interactions identify two novel genes, SLA1 and SLA2, that control membrane cytoskeleton assembly in Saccharomyces cerevisiae. J. Cell Biol. 122, 635–644 (1993).

    Article  CAS  Google Scholar 

  21. Kalchman, M.A. et al. Huntingtin is ubiquitinated and interacts with a specific ubiquitin conjugated enzyme. J. Biol. Chem. 271, 19385–19394 (1996).

    Article  CAS  Google Scholar 

  22. Li, X.-J. et al. A huntingtin-associated protein enriched in brain with implications for pathology. Nature 378, 398–402 (1995).

    Article  CAS  Google Scholar 

  23. Na, S., Hincapie, M., McCusker, J.H. & Haber, J.E. MOP2 (SLA2) affects the abundance of the plasma membrane H+-ATPase of Saccharomyces cerevisiae. J. Biol. Chem. 270, 375–443 (1995).

    Article  Google Scholar 

  24. Raths, S., Rohrer, J., Crausaz, F. & Riezman, H. end3 and end4: Two mutants defective in receptor-mediated and fluid-phase endocytosis in Saccharomyces cervisiae. J. Cell Biol. 120, 55–65 (1993).

    Article  CAS  Google Scholar 

  25. Pearlman, J.A., Powaser, P.A., Caskey, C.T. Troponin T is capable of binding dystrophin via a leucine zipper. FEBS Letters 354, 183–186 (1994).

    Article  CAS  Google Scholar 

  26. John, M., Briand, J.P., Granger-Schnarr, M. & Schnarr, M. Two pairs of oppositely charged amino acids from Jun and Fos confer heterodimerization to GCN4 leucine zipper. J. Biol. Chem. 269, 16247–16253 (1994).

    CAS  PubMed  Google Scholar 

  27. Rees, D.J., Ades, S.E., Singer, S.J. & Hynes, R.O. Sequence and domain structure of talin. Nature 347, 18–63 (1990).

    Article  Google Scholar 

  28. Nasir, J. et al. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81, 811–823 (1995).

    Article  CAS  Google Scholar 

  29. Hodgson, J.G. et al. Human huntingtin derived from YAC transgenes compensates for loss of murine huntingtin by rescue of the embryonic lethal phenotype. Hum. Mol. Genet. 5, 1875–1885 (1996).

    Article  CAS  Google Scholar 

  30. Rabizadeh, S. et al. Mutations associated with amyotrophic lateral sclerosis convert superoxide dismutase from an antiapoptotic gene to a proapoptotic gene: studies in yeast and neural cells. Proc Natl. Acad. Sci. USA. 92, 3024–3028 (1995).

    Article  CAS  Google Scholar 

  31. Morrow, D.M., Tagle, D.A., Shiloh, Y., Collins, F.S. & Hieter, P. TEL1, an S. cerevisiae homologue of the human gene mutated in ataxia telangiectasia, is functionally related to the yeast checkpoint gene MEC1. Cell 82, 831–840 (1995).

    Article  CAS  Google Scholar 

  32. Towbin, H., Staehelin, T. & Gordon, J. Electrophoretic transfer of proteins form polyacrylamide gels to nitrocellulose sheets: Procedure and some applications. Proc. Natl. Acad. Sci. USA. 76, 100–104 (1979).

    Article  Google Scholar 

  33. Shull, G.E., Schwartz, A. & Lingrel, J.B. Amino-acid sequence of the catalytic subunit of the (Na+ + K+)ATPase deduced from a complementary DNA. Nature 316, 33–34 (1985).

    Article  Google Scholar 

  34. MacLennan, D.H., Brandl, C.J., Korczak, B. & Green, N.M., Calcium ATPases: contribution of molecular genetics to our understanding of structure and function. Soc. Gen. Phys. Ser. 41, 287–300 (1987).

    CAS  Google Scholar 

  35. Brandl, C.J., Green, N.M., Korczak, B. & MacLennan, D.H., Two Ca2+ ATPase genes: homologies and mechanistic implications of deduced amino acid sequences. Cell 44, 597–607 (1986).

    Article  CAS  Google Scholar 

  36. Wood, J.D., Harper, P.S. & Jones, A.L. Characteristics of cytosolic and membrane bound forms of huntingtin. Am. J. Hum. Genet. 59, A295(1996).

    Google Scholar 

  37. Wood, J.D., MacMillan, J.C., Harper, P.S., Lowenstein, P.R. & Jones, A.L. Partial characterisation of murine huntingtin and apparent variations in the subcellular localisation of huntingtin in human, mouse and rat brain. Hum. Mol. Genet. 5, 418–487 (1996).

    Article  Google Scholar 

  38. Bhide, P.G. et al. Expression of normal and mutant huntingtin in the developing brain. J. Neurosci. 16, 5523–5535 (1996).

    Article  CAS  Google Scholar 

  39. Burke, J.R. et al. Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nature Med. 2, 347–350 (1996).

    Article  CAS  Google Scholar 

  40. Sirover, M.A. Emerging new functions of the glycolytic protein, glyceraldehyde-3-phosphate dehydrogenase, in mammalian cells. Life Sci. 58, 2271–2277 (1996).

    Article  CAS  Google Scholar 

  41. Koshy, B. et al. Spinocerebellar ataxia type-1 and spinobulbar muscular atrophy gene products interact with glyceraldehyde-3-phosphate dehydrogenase. Hum. Mol. Genet. 5, 1311–1318 (1996).

    Article  CAS  Google Scholar 

  42. Nasir, J., Goldberg, Y.P. & Hayden, M.R. Huntington disease: new insights into the relationship between CAG expansion and disease. Hum. Mol. Genet. 5, 1431–1435 (1996).

    Article  CAS  Google Scholar 

  43. Goldberg, Y.P. et al. Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nature Genet. 13, 442–449 (1996).

    Article  CAS  Google Scholar 

  44. Goldberg, Y. et al. Absence of disease phenotype and intergenerational stability of the CAG repeat in transgenic mice expressing the human Huntington disease transcript. Hum. Mol. Genet. 5, 177–185 (1996).

    Article  CAS  Google Scholar 

  45. Durfee, T. et al. The retinoblastoma protein associates with the protein phosphatase type 1 catalystic subunit. Genes & Develop. 7, 555–569 (1993).

    Article  CAS  Google Scholar 

  46. Gietz, R.D., Woods, R.A., Manivasakam, P. & Schiestl, R.H. Yeast growth and yeast transformation. in Cell Biology: A Laboratory Manual (eds Spector, D., Goldman, R. & Leinwand, L.) (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1996). In press.

    Google Scholar 

  47. Suzuki, T. et al. Regional and cellular presenilin 1 gene expression in human and rat tissues. Biochem. Biophys. Res. Comm. 219, 708–713 (1996).

    Article  CAS  Google Scholar 

  48. Lin, B. et al. Differential 3′ polyadenylation of the Huntington disease gene results in two mRNA species with variable tissue expression. Hum. Mol. Genet. 2, 1541–1545 (1993).

    Article  CAS  Google Scholar 

  49. Arai, M. & Cohen, J.A. Subcellular localization of the F5 protein to the neuronal membrane-associated cytoskeleton. J. Neurosc. Res. 38, 348–357 (1994).

    Article  CAS  Google Scholar 

  50. Wanker, E. et al. HIP-1: A huntingtin interacting protein isolated by the yeast two-hybrid system. Hum. Mol. Genet. 6, 487–495 (1997).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Genetics, University of British Columbia, NCE Building, Room 416,2125 East Mall, Vancouver, British Columbia, Canada, V6T 1Z4

    Michael A. Kalchman, H. Brook Koide, Krista McCutcheon, Rona K. Graham, Kerrie Nichol, Parsa Kazemi-Esfarjani, Francis C. Lynn, Cheryl Wellington, Martina Metzler, Y. Paul Goldberg & Michael R. Hayden

  2. Department of Clinical Neurology and Neuroscience, Faculty of Medicine, University of Tokyo, Tokyo, 113, Japan

    Kazutoshi Nishiyama & Ichiro Kanazawa

  3. Department of Human Genetics, Faculty of Medicine, University of Manitoba, Room 250, 770 Bannatyne Avenue, Winnipeg, Manitoba, Canada, R3E OW3

    R. Dan. Gietz

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  1. Michael A. Kalchman
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Kalchman, M., Koide, H., McCutcheon, K. et al. HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain. Nat Genet 16, 44–53 (1997). https://doi.org/10.1038/ng0597-44

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