Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities.
The mechanisms of pathology for the family of polyglutamine disease proteins are unknown; however, recently it was shown that several of these proteins inhibit transcription suggesting that transcriptional repression may be a potential mechanism for pathology. In the present study we use cell transfections, in vitro binding, co-immunoprecipitations, and reporter assays to show that the polyglutamine disease protein, ataxin-3, interacts with the major histone acetyltransferases cAMP-response-element binding protein (CREB)-binding protein, p300, and p300/CREB-binding protein-associated factor and inhibits transcription by these coactivators. Importantly, endogenous ataxin-3 is co-immunoprecipitated with each of these coactivators in non-transfected cells. The C-terminal polyglutamine-containing domain of ataxin-3 inhibits coactivator-dependent transcription and is required for binding coactivators. The N-terminal domain of ataxin-3 inhibits histone acetylation by p300 in vitro and inhibits transcription in vivo. Histone binding and blocking access of coactivators to acetylation sites on histones appears to be the mechanism of inhibition. Together, our data provide a novel mechanism of transcriptional regulation by ataxin-3 that involves targeting histones, coactivators, and an independent mode of direct repression of transcription, and suggests that its physiological function and possibly pathological effects are linked to its interactions with these proteins.
Li
Fusheng
F
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084, USA.
Macfarlan
Todd
T
Pittman
Randall N
RN
Chakravarti
Debabrata
D
D000123:Acetyltransferases / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D000067699:Ataxin-3; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D050881:E1A-Associated p300 Protein; D017930:Genes, Reporter; D051548:Histone Acetyltransferases; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000503:physiopathology; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D000067699:Ataxin-3; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D017362:Cyclic AMP Response Element-Binding Protein; D050881:E1A-Associated p300 Protein; D051548:Histone Acetyltransferases; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C494361:Ep300 protein, mouse; C092341:ATXN3 protein, human; C511594:Atxn3 protein, mouse