Huntingtin contains a highly conserved nuclear export signal.
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.
Xia
Jianrun
J
Department of Biochemistry, McMaster University, Health Sciences Centre Rm 4H45, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5.
Lee
Denise H
DH
Taylor
Jillian
J
Vandelft
Mark
M
Truant
Ray
R
D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival; D017124:Conserved Sequence; D003593:Cytoplasm / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism*; D018715:Microscopy, Video; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000473:pathology; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D017384:Sequence Deletion; D019680:Trinucleotide Repeat Expansion
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine