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Xia, J, Lee, DH, Taylor, J, Vandelft, M and Truant, R (2003) Huntingtin contains a highly conserved nuclear export signal. Hum. Mol. Genet. 12:1393-403


Huntington's disease (HD), is a genetic neurodegenerative disease characterized by a DNA CAG triplet repeat expansion in the first exon of the disease gene, HD. CAG DNA expansion results in a polyglutamine tract expansion in mutant huntingtin protein. Wild-type and mutant full-length huntingtin have been detected in the nucleus, but elevated levels of mutant huntingtin and huntingtin amino-terminal proteolytic fragments are seen to accumulate in the nuclei of HD-affected neurons. The presence of huntingtin in both the nucleus and the cytoplasm suggested that huntingtin may be dynamic between these compartments. By live cell time-lapse video microscopy, we have been able to visualize polyglutamine-mediated aggregation and the transient nuclear localization of huntingtin over time in a striatal cell line. A classical nuclear localization signal could not be detected in huntingtin, but we have discovered a nuclear export signal (NES) in the carboxy-terminus of huntingtin. Leptomycin B treatment of clonal striatal cells enhanced the nuclear localization of huntingtin, and a mutant NES huntingtin displayed increased nuclear localization, indicating that huntingtin can shuttle to and from the nucleus. The huntingtin NES is strictly conserved among all huntingtin proteins from diverse species. This export signal may be important in Huntington's disease because this fragment of huntingtin is proteolytically cleaved away during HD. The huntingtin NES therefore defines a potential role for huntingtin as a member of a nucleocytoplasmic dynamic protein complex.




Active Transport, Cell Nucleus; Cell Nucleus/metabolism; Cell Nucleus/pathology; Cell Survival; Conserved Sequence; Cytoplasm/pathology; HeLa Cells; Humans; Huntington Disease/metabolism; Microscopy, Video; Nerve Tissue Proteins/metabolism; Neurons/pathology; Nuclear Localization Signals; Nuclear Proteins/metabolism; Peptides/genetics; Peptides/metabolism; Protein Transport; Sequence Deletion; Trinucleotide Repeat Expansion



Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status


GO:0046825: regulation of protein export from nucleus



Figure 1 shows the analysis of a putative nuclear localization signal of huntingtin in an in vivo assay of human HeLa epithelial cells. It does not contain a classic nuclear localization signal.

CACAO 9328



GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion


Seeded From UniProt


See also


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