Ataxin-7 can export from the nucleus via a conserved exportin-dependent signal.
Spinocerebellar ataxia type 7 is a progressive neurodegenerative disorder caused by a CAG DNA triplet repeat expansion leading to an expanded polyglutamine tract in the ataxin-7 protein. Ataxin-7 appears to be a transcription factor and a component of the STAGA transcription coactivator complex. Here, using live cell imaging and inverted fluorescence recovery after photobleaching, we demonstrate that ataxin-7 has the ability to export from the nucleus via the CRM-1/exportin pathway and that ataxin-7 contains a classic leucine-type nuclear export signal (NES). We have precisely defined the location of this NES in ataxin-7 and found it to be fully conserved in all vertebrate species. Polyglutamine expansion was seen to reduce the nuclear export rate of mutant ataxin-7 relative to wild-type ataxin-7. Subtle point mutation of the NES in polyglutamine expanded ataxin-7 increased toxicity in primary cerebellar neurons in a polyglutamine length-dependent manner in the context of full-length ataxin-7. Our results add ataxin-7 to a growing list of polyglutamine disease proteins that are capable of nuclear shuttling, and we define an activity of ataxin-7 in the STAGA complex of trafficking between the nucleus and cytoplasm.
Taylor
Jillian
J
Department of Biochemistry and Biomedical Sciences, McMaster University, HSC4H45 Hamilton, Ontario L8N3Z5 Canada.
Grote
Sara K
SK
Xia
Jianrun
J
Vandelft
Mark
M
Graczyk
Joanna
J
Ellerby
Lisa M
LM
La Spada
Albert R
AR
Truant
Ray
R
D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus; D000818:Animals; D000067719:Ataxin-7; D002526:Cerebellar Diseases / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology; D017124:Conserved Sequence; D006801:Humans; D028884:Karyopherins / Q000737:chemistry*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D049790:Nuclear Export Signals / Q000235:genetics; D010455:Peptides / Q000494:pharmacology; D017354:Point Mutation; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry*; D014157:Transcription Factors; D014162:Transfection; D000097606:Exportin 1 Protein
D000067719:Ataxin-7; D028884:Karyopherins; D009419:Nerve Tissue Proteins; D049790:Nuclear Export Signals; D010455:Peptides; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000097606:Exportin 1 Protein; C000593829:ATXN7 protein, human; C000593831:Atxn7 protein, mouse; C097188:polyglutamine