TSF3 encodes one of six (TSF1 to TSF6) recently identified global negative regulators of transcription in Saccharomyces cerevisiae. Mutant tsaf strains exhibit defects in transcriptional silencing of the GAL) promoter, allow expression from upstream activation sequence-less promoters, and exhibit pleiotropic defects in cell growth and development. Here we show that TSF3 is involved in transcriptional silencing mediated
Spinocerebellar ataxia type 3 (SCA3) belongs to the family of polyglutamine neurodegenerations. Each disorder stems from the abnormal lengthening of a glutamine repeat in a different protein. Although caused by a similar mutation, polyglutamine disorders are distinct, implicating non-polyglutamine regions of disease proteins as regulators of pathogenesis. SCA3 is caused by polyglutamine expansion in ataxin-3. To determine the role of ataxin-3’s non-polyglutamine domains in disease, we utilized a new, allelic series of Drosophila melanogaster. We found that ataxin-3 pathogenicity is saliently controlled by polyglutamine-adjacent ubiquitin-interacting motifs (UIMs) that enhance aggregation and toxicity. UIMs function by interacting with the heat shock protein, Hsc70-4, whose reduction diminishes ataxin-3 toxicity in a UIM-dependent manner. Hsc70-4 also enhances pathogenicity of other polyglutamine proteins. Our studies provide a unique insight into the impact of ataxin-3 domains in SCA3, identify Hsc70-4 as a SCA3 enhancer, and indicate pleiotropic effects from HSP70 chaperones, which are generally thought to suppress polyglutamine degeneration.
The small modifier protein, ubiquitin, holds a special place in eukaryotic biology because of its myriad post-translational effects that control normal cellular processes and are implicated in various diseases. By being covalently conjugated onto other proteins, ubiquitin changes their interaction landscape-fostering new interactions as well as inhibiting others-and ultimately deciding the fate of its substrates and controlling pathways that span most cell physiology. Ubiquitin can be attached onto other proteins as a monomer or as a poly-ubiquitin chain of diverse structural topologies. Among the types of poly-ubiquitin species generated are ones detached from another substrate-comprising solely ubiquitin as their constituent-referred to as unanchored, or free chains. Considered to be toxic byproducts, these species have recently emerged to have specific physiological functions in immune pathways and during cell stress. Free chains also do not appear to be detrimental to multi-cellular organisms; they can be active members of the ubiquitination process, rather than corollary species awaiting disassembly into mono-ubiquitin. Here, we summarize past and recent studies on unanchored ubiquitin chains, paying special attention to their emerging roles as second messengers in several signaling pathways. These investigations paint complex and flexible outcomes for free ubiquitin chains, and present a revised model of unanchored poly-ubiquitin biology that is in need of additional investigation.
Of the family of polyglutamine (polyQ) neurodegenerative diseases, Spinocerebellar Ataxia Type 3 (SCA3) is the most common. Like other polyQ diseases, SCA3 stems from abnormal expansions in the CAG triplet repeat of its disease gene resulting in elongated polyQ repeats within its protein, ataxin-3. Various ataxin-3 protein domains contribute to its toxicity, including the valosin-containing protein (VCP)-binding motif (VBM). We previously reported that VCP, a homo-hexameric protein, enhances pathogenic ataxin-3 aggregation and exacerbates its toxicity. These findings led us to explore the impact of targeting the SCA3 protein by utilizing a decoy protein comprising the N-terminus of VCP (N-VCP) that binds ataxin-3’s VBM. The notion was that N-VCP would reduce binding of ataxin-3 to VCP, decreasing its aggregation and toxicity. We found that expression of N-VCP in
Drosophila melanogaster
models of SCA3 ameliorated various phenotypes, coincident with reduced ataxin-3 aggregation. This protective effect was specific to pathogenic ataxin-3 and depended on its VBM. Increasing the amount of N-VCP resulted in further phenotype improvement. Our work highlights the protective potential of targeting the VCP-ataxin-3 interaction in SCA3, a key finding in the search for therapeutic opportunities for this incurable disorder.
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