title: Poly(Q) Expansions in ATXN7 Affect Solubility but Not Activity of the SAGA Deubiquitinating Module.
abstract: Spinocerebellar ataxia type 7 (SCA7) is a debilitating neurodegenerative disease caused by expansion of a polyglutamine [poly(Q)] tract in ATXN7, a subunit of the deubiquitinase (DUB) module (DUBm) in the SAGA complex. The effects of ATXN7-poly(Q) on DUB activity are not known. To address this important question, we reconstituted the DUBm in vitro with either wild-type ATXN7 or a pathogenic form, ATXN7-92Q NT, with 92 Q residues at the N terminus (NT). We found that both forms of ATXN7 greatly enhance DUB activity but that ATXN7-92Q NT is largely insoluble unless it is incorporated into the DUBm. Cooverexpression of DUBm components in human astrocytes also promoted the solubility of ATXN7-92Q, inhibiting its aggregation into nuclear inclusions that sequester DUBm components, leading to global increases in ubiquitinated H2B (H2Bub) levels. Global H2Bub levels were also increased in the cerebellums of mice in a SCA7 mouse model. Our findings indicate that although ATXN7 poly(Q) expansions do not change the enzymatic activity of the DUBm, they likely contribute to SCA7 by initiating aggregates that sequester the DUBm away from its substrates.
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, Center for Cancer Epigenetics, University of Texas M. D. Anderson Cancer Center, Smithville, Texas, USA.
authors.forename: Xianjiang
authors.initials: X
authors.lastname: Lan
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, Center for Cancer Epigenetics, University of Texas M. D. Anderson Cancer Center, Smithville, Texas, USA.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Koutelou
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, Center for Cancer Epigenetics, University of Texas M. D. Anderson Cancer Center, Smithville, Texas, USA.
authors.forename: Andria C
authors.initials: AC
authors.lastname: Schibler
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yi Chun
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Grant
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, Center for Cancer Epigenetics, University of Texas M. D. Anderson Cancer Center, Smithville, Texas, USA sroth@mdanderson.org.
authors.forename: Sharon Y R
authors.initials: SY
authors.lastname: Dent
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D000067719:Ataxin-7; D002531:Cerebellum / Q000378:metabolism; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D061987:Sf9 Cells; D012995:Solubility; D020754:Spinocerebellar Ataxias / Q000378:metabolism* / Q000473:pathology; D018411:Spodoptera; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine; D064570:Ubiquitin-Specific Proteases