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Ataxin 1 (Atx1) is a foci-forming polyglutamine protein of unknown function, whose mutant form causes type 1 spinocerebellar ataxia in humans and exerts neurotoxicity in transgenic mouse and fly expressing mutant Atx1. In this study, we demonstrate that Atx1 interacts with the transcriptional corepressor SMRT (silencing mediator of retinoid and thyroid hormone receptors) and with histone deacetylase 3. Atx1 binds chromosomes and mediates transcriptional repression when tethered to DNA. Interaction with SMRT-related factors is a conserved feature of Atx1, because Atx1 also binds SMRTER, a Drosophila cognate of SMRT. Significantly, mutant Atx1 forms aggregates in Drosophila , and such mutant Atx1-mediated aggregates sequester SMRTER. Consistently, the neurodegenerative eye phenotype caused by mutant Atx1 is enhanced by a Smrter mutation and, conversely, is suppressed by a chromosomal duplication that contains the wild type Smrter gene. Together, our results suggest that Atx1 is a transcriptional factor whose mutant form exerts its deleterious effects in part by perturbing corepressor-dependent transcriptional pathways.

The complement C5a pathway has been shown to be an important mediator of inflammation and tissue injury. To further understand the role of C5a receptor (C5aR) pathway in ischemia/reperfusion (I/R) injury, and to evaluate the potential of antagonizing C5aR to protect from I/R injury, we tested the effect of eliminating C5aR using C5aR knockout (KO) mice and their wild-type (WT) littermates in a superior mesenteric artery occlusion (SMAO) intestinal I/R injury model. C5aR KO and WT mice were subjected to SMAO or sham for 45 min. After 3 h of reperfusion, the percentage of injured ileal villi was twice as high in WT mice subjected to SMAO as compared with the C5aR KO mice. In addition, the number of neutrophils was 34% higher in WT mice subjected to SMAO as compared with the C5aR KO mice. Moreover, ileum and lung myeloperoxidase activities after SMAO were significantly higher in WT than C5aR KO mice. Apoptotic cell death was induced after reperfusion in WT-SMAO and was reduced by more than 50% in C5aR KO mice. The plasma level of TNF-alpha was increased approximately 3.74-fold in WT subjected to SMAO compared with sham. In contrast, the level was increased only approximately 1.18-fold in the C5aR KO mice subjected to SMAO. In conclusion, this study demonstrates that elimination of the C5aR pathway protects the intestine from I/R injury and diminishes intestine-derived pulmonary neutrophil sequestration. Blocking C5aR may be considered as a potential therapeutic intervention for I/R injury.

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-1 and Atrophin-2. Atrophin interacts with Tll physically and genetically, and both proteins localize to the same knirps promoter region. Because Atrophin proteins interact with additional nuclear receptors and Atrophin-2 selectively binds histone deacetylase 1/2 (HDAC1/2) through its ELM2 (EGL-27 and MTA1 homology 2)/SANT (SWI3/ADA2/N-CoR/TFIII-B) domains, our study establishes that Atrophin proteins represent a novel class of nuclear receptor corepressors.

Ataxin-1 is a neurodegenerative disorder protein whose glutamine-repeat expanded form causes spinocerebellar ataxia type 1 (SCA1) in humans and exerts cytotoxicity in Drosophila and mouse. We report here that the cytotoxicity caused by ataxin-1 is modulated by association with a related protein, Brother of ataxin-1 (Boat). Boat and ataxin-1 share a conserved AXH (ataxin-1 and HMG-box protein 1) domain, which is essential for both proteins' interactions with the transcriptional corepressor SMRT and its Drosophila homolog, SMRTER. The Boat-ataxin-1 interaction is mediated through multiple regions in both proteins, including a newly identified NBA (N-terminal region of Boat and ataxin-1) domain. We investigated the physiological relevance of the Boat-ataxin-1 interaction in Drosophila and discovered that a mutant ataxin-1-mediated eye defect is suppressed by ataxin-1's association with Boat. Correspondingly, in transgenic SCA1 mouse, Boat expression is greatly reduced in Purkinje cells, the primary targets of SCA1. Our study thus establishes that Boat is an in vivo binding partner of ataxin-1 whose altered expression in Purkinje cells may contribute to their degeneration in SCA1 animals.