SUMO-targeted ubiquitin ligases (STUbLs) play an important role in the homeostasis of SUMO-modified proteins and SUMO-dependent signaling. Eukaryotic cells that lack STUbLs are hypersensitive to DNA damage, and accumulate gross chromosomal rearrangements and high-molecular weight adducts of SUMO-modified proteins. In this study we show that budding yeast STUbLs (Slx5 and Slx8) also modulate the aggregation, toxicity, and transcriptional properties of poly-glutamine (poly-Q) expanded huntingtin (Htt), the causative agent of Huntington’s Disease (HD). We demonstrate that expression of an aggregation-prone Htt construct with 103 glutamine residues (103Q), but not the non-expanded form (25Q), results in severe growth defects in slx5∆ and slx8∆ cells. Concomitantly, an extra copy of SLX5 reduces the accumulation of 103Q aggregates in the cytosol of wild type cells while overexpression of SUMO led to diffuse nuclear staining of Htt. This nuclear enrichment of Htt prompted us to assess the effect of STUbLs on the transcriptional properties of 25Q, 55Q and 97Q. Expression of 25Q, 55Q and 97Q fused to the Gal4 activation domain (AD) resulted in reporter gene auto-activation. Remarkably, the auto-activation of Htt constructs was abolished by expression of Slx5 fused to the Gal4 DNA-binding domain (Slx5-BD) but not an Slx5 SIM mutant (BD-Slx5sim) that fails to interact non-covalently with SUMO. These data suggest a novel role for STUbLs in the recently described proteolysis-independent stripping of transcription factors that also involves Cdc48 and its co-factors.