Polyglutamine expansion of huntingtin impairs its nuclear export.
Proteins with polyglutamine (polyQ) expansions accumulate in the nucleus and affect gene expression. The mechanism by which mutant huntingtin (htt) accumulates intranuclearly is not known; wild-type htt, a 350-kDa protein of unknown function, is normally found in the cytoplasm. N-terminal fragments of mutant htt, which contain a polyQ expansion (>37 glutamines), have no conserved nuclear localization sequences or nuclear export sequences but can accumulate in the nucleus and cause neurological problems in transgenic mice. Here we report that N-terminal htt shuttles between the cytoplasm and nucleus in a Ran GTPase-independent manner. Small N-terminal htt fragments interact with the nuclear pore protein translocated promoter region (Tpr), which is involved in nuclear export. PolyQ expansion and aggregation decrease this interaction and increase the nuclear accumulation of htt. Reducing the expression of Tpr by RNA interference or deletion of ten amino acids of N-terminal htt, which are essential for the interaction of htt with Tpr, increased the nuclear accumulation of htt. These results suggest that Tpr has a role in the nuclear export of N-terminal htt and that polyQ expansion reduces this nuclear export to cause the nuclear accumulation of htt.
Cornett
Jonathan
J
Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia 30322, USA.
Cao
Fengli
F
Wang
Chuan-En
CE
Ross
Christopher A
CA
Bates
Gillian P
GP
Li
Shi-Hua
SH
Li
Xiao-Jiang
XJ
D000595:Amino Acid Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D028861:Nuclear Pore Complex Proteins / Q000737:chemistry; D010455:Peptides / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D028861:Nuclear Pore Complex Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; C073597:TPR protein, human; C097188:polyglutamine