| RRC ID |
15591
|
| Author |
Chan WM, Tsoi H, Wu CC, Wong CH, Cheng TC, Li HY, Lau KF, Shaw PC, Perrimon N, Chan HY.
|
| Title |
Expanded polyglutamine domain possesses nuclear export activity which modulates subcellular localization and toxicity of polyQ disease protein via exportin-1.
|
| Journal |
Hum Mol Genet
|
| Abstract |
Polyglutamine (polyQ) diseases are a group of late-onset, progressive neurodegenerative disorders caused by CAG trinucleotide repeat expansion in the coding region of disease genes. The cell nucleus is an important site of pathology in polyQ diseases, and transcriptional dysregulation is one of the pathologic hallmarks observed. In this study, we showed that exportin-1 (Xpo1) regulates the nucleocytoplasmic distribution of expanded polyQ protein. We found that expanded polyQ protein, but not its unexpanded form, possesses nuclear export activity and interacts with Xpo1. Genetic manipulation of Xpo1 expression levels in transgenic Drosophila models of polyQ disease confirmed the specific nuclear export role of Xpo1 on expanded polyQ protein. Upon Xpo1 knockdown, the expanded polyQ protein was retained in the nucleus. The nuclear disease protein enhanced polyQ toxicity by binding to heat shock protein (hsp) gene promoter and abolished hsp gene induction. Further, we uncovered a developmental decline of Xpo1 protein levels in vivo that contributes to the accumulation of expanded polyQ protein in the nucleus of symptomatic polyQ transgenic mice. Taken together, we first showed that Xpo1 is a nuclear export receptor for expanded polyQ domain, and our findings establish a direct link between protein nuclear export and the progressive nature of polyQ neurodegeneration.
|
| Volume |
20(9)
|
| Pages |
1738-50
|
| Published |
2011-5-1
|
| DOI |
10.1093/hmg/ddr049
|
| PII |
ddr049
|
| PMID |
21300695
|
| MeSH |
Active Transport, Cell Nucleus
Animals
Cell Line
Cell Nucleus / genetics
Cell Nucleus / metabolism*
Disease Models, Animal*
Drosophila* / genetics
Drosophila* / metabolism
HEK293 Cells
Humans
Intracellular Space / genetics
Intracellular Space / metabolism*
Karyopherins / genetics
Karyopherins / metabolism*
Neurodegenerative Diseases / genetics
Neurodegenerative Diseases / metabolism*
Peptides / genetics
Peptides / metabolism*
Protein Binding
Protein Structure, Tertiary
Protein Transport
Proteins / chemistry
Proteins / genetics
Proteins / metabolism*
Proteins / toxicity
Receptors, Cytoplasmic and Nuclear / genetics
Receptors, Cytoplasmic and Nuclear / metabolism*
Trinucleotide Repeat Expansion
|
| IF |
5.101
|
| Times Cited |
22
|
|
WOS Category
|
GENETICS & HEREDITY
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| Resource |
| Drosophila |
13387R-1
13387R-4 |
