title: Expanded polyglutamine domain possesses nuclear export activity which modulates subcellular localization and toxicity of polyQ disease protein via exportin-1.
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.
authors.affiliation: Laboratory of Drosophila Research, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Wing Man
authors.initials: WM
authors.lastname: Chan
authors.forename: Ho
authors.initials: H
authors.lastname: Tsoi
authors.forename: Chi Chung
authors.initials: CC
authors.lastname: Wu
authors.forename: Chi Hang
authors.initials: CH
authors.lastname: Wong
authors.forename: Tat Cheung
authors.initials: TC
authors.lastname: Cheng
authors.forename: Hoi Yeung
authors.initials: HY
authors.lastname: Li
authors.forename: Kwok Fai
authors.initials: KF
authors.lastname: Lau
authors.forename: Pang Chui
authors.initials: PC
authors.lastname: Shaw
authors.forename: Norbert
authors.initials: N
authors.lastname: Perrimon
authors.forename: Ho Yin Edwin
authors.initials: HY
authors.lastname: Chan
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000235:genetics / Q000378:metabolism*; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion; D000097606:Exportin 1 Protein
chemical_list: D028884:Karyopherins; D010455:Peptides; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C097188:polyglutamine