A hallmark of most neurodegenerative diseases, including those caused by polyglutamine expansion, is the formation of ubiquitin (Ub)-positive protein aggregates in affected neurons. This finding suggests that the Ub system may be involved in common mechanisms underlying these otherwise unrelated diseases. Here we report the finding of ataxin-3 (Atx-3), whose mutation is implicated in the neurodegenerative disease spinocerebellar ataxia type 3, in a bioinformatics search of the human genome for components of the Ub system. We show that wild-type Atx-3 is a Ub-binding protein and that the interaction of Atx-3 with Ub is mediated by motifs homologous to those found in a proteasome subunit. Both wild-type Atx-3 and the otherwise unrelated Ub-binding protein p62͞Sequestosome-1 have been shown to be sequestered into aggregates in affected neurons in several neurodegenerative diseases, but the mechanism for this recruitment has remained unclear. In this article, we show that functional Ub-binding motifs in Atx-3 and p62 proteins are required for the localization of both proteins into aggregates in a cell-based assay that recapitulates several features of polyglutamine disease. We propose that the Ub-mediated sequestration of essential Ub-binding protein(s) into aggregates may be a common mechanism contributing to the pathogenesis of neurodegenerative diseases.
Drosophila Tailless (Tll) is an orphan nuclear receptor involved in embryonic segmentation and neurogenesis. Although Tll exerts potent transcriptional repressive effects, the underlying molecular mechanisms have not been determined. Using the established regulation of knirps by tll as a paradigm, we report that repression of knirps by Tll involves Atrophin, which is related to vertebrate Atrophin
Atrophin family proteins, including the vertebrate arginineglutamic acid dipeptide repeats protein (RERE) and Drosophila Atrophin (Atro), constitute a new class of nuclear receptor corepressors. Both RERE and Atro share the ELM2 (EGL-27 and MTA1 homology 2) and SANT (SWI3/ADA2/N-CoR/TFIII-B) domains, which are also present in other important transcriptional cofactors. Here, we report that the SANT domain in RERE binds to the histone methyltransferase G9a, and that both the ELM2 and SANT domains orchestrate molecular events that lead to a stable methylation of histone H3-lysine 9. We establish the physiological relevance of these interactions among Atrophin, G9a, and histone deacetylases 1 and 2 in Drosophila by showing that these proteins localize to overlapping chromosomal loci, and act together to suppress wing vein and melanotic-mass formation. This study not only shows a new function of the SANT domain and establishes its connection with the ELM2 domain, but also implies that a similar strategy is used by other ELM2-SANT proteins to repress gene transcription and to exert biological effects.
(LW), present addressThe normal development and physiological functions of multicellular organisms are regulated by complex gene transcriptional networks that include myriad transcription factors, their associating coregulators, and multiple chromatin-modifying factors. Aberrant gene transcriptional regulation resulting from mutations among these elements often leads to developmental defects and diseases. This review article concentrates on the Atrophin family proteins, including vertebrate Atrophin-1 (ATN1), vertebrate arginine-glutamic acid dipeptide repeats protein (RERE), and Drosophila Atrophin (Atro), which we recently identified as nuclear receptor corepressors. Disruption of Atrophin-mediated pathways causes multiple developmental defects in mouse, zebrafish, and Drosophila, while an aberrant form of ATN1 and altered expression levels of RERE are associated with neurodegenerative disease and cancer in humans, respectively. We here provide an overview of current knowledge about these Atrophin proteins. We hope that this information on Atrophin proteins may help stimulate fresh ideas about how this newly identified class of nuclear receptor corepressors aids specific nuclear receptors and other transcriptional factors in regulating gene transcription, manifesting physiological effects, and causing diseases. Received July 10th, 2008; Accepted September 22nd, 2008; Published November 7th, 2008 | Abbreviations: AIP: ATN1-interacting protein; AML: acute myeloid leukemia; ASH1: absent, small, or homeotic discs 1; ATN1: Atrophin-1; Atro: Atrophin; BAH: bromo adjacent homology; Bks: Brakeless; CHD4: chromodomain helicase DNA binding protein 4; CoREST: corepressor of REST; COUP-TF: chicken ovalbumin upstream promoter-transcription factor; DBD: DNA binding domain; DRPLA: dentatorubral-phallidolusian atrophy; EcR: ecdysone receptor; EGFR: epidermal growth factor receptor; ELM2: EGL-27 and MTA1 homology 2; Eve: Even-skipped; fgf8: fibroblast growth factor 8; ftz: fushi-tarazu; HDAC: histone deacetylase; HEF1: human enhancer of filamentation 1; HMTase: histone methyltransferase; IRSp53: insulin receptor tyrosine kinase substrate protein of 53kD; KD: lysine-aspartic acid; KE: lysine-glutamic acid; kni: knirps; LBD: ligand binding domain; LSD1: lysine specific demethylase 1; MBD: methyl CpG binding protein; MIER1: mesoderm induction early response 1; MTA: metastasis-associated protein; N-CoR: nuclear receptor corepressor; NuRD: nucleosome remodeling and histone deacetylase; Orc1: origin recognition complex 1; PBAF: polybromo, BRG-1 associated factors; PcG: polycomb group; PPAR: peroxisome proliferator-activated receptor; RAR: retinoic acid receptor; RD: arginin-aspartic acid; RERE: arginine glutamic acid repeats encoded protein; RE-repeats: arginine-glutamic acid dipeptide repeats; REST: RE1-silencing transcriptional factor; RSC: remodeling the structure of chromatin; RXR: retinoid-X receptor; SANT: SWI3/ADA2/N-CoR/TFIII-B; Sbb: Scribbler; SH3: Src homology 3; Sir: silent information regulator; SMRT: silencing mediato...
Ataxin-1 (ATXN1), a causative factor for spinocerebellar ataxia type 1 (SCA1), and the related Brother of ATXN1 (BOAT1) are human proteins involved in transcriptional repression. So far, little is known about which transcriptional pathways mediate the effects of ATXN1 and BOAT1. From our analyses of the properties of BOAT1 in Drosophila and of both proteins in mammalian cells, we report here that BOAT1 and ATXN1 are components of the Notch signalling pathway. In Drosophila, BOAT1 compromises the activities of Notch. In mammalian cells, both ATXN1 and BOAT1 bind to the promoter region of Hey1 and inhibit the transcriptional output of Notch through direct interactions with CBF1, a transcription factor that is crucial for the Notch pathway. Our results suggest that, in addition to their involvement in SCA1, ATXN1 and BOAT1 might participate in several Notch-controlled developmental and pathological processes.
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