Ubiquilin proteins contain an ubiquitin-like domain (UBL) and ubiquitin-associated (UBA) domain that interact with the proteasome and ubiquitinated substrates, respectively. Previous works have established the link of ubiquilin proteins to several neurodegenerative diseases, but their molecular function remains elusive. Here, we used misfolded Huntingtin exon I containing 103 polyglutamine expansion (Htt103QP) as a misfolded protein substrate to investigate the function of ubiquilin proteins. We found that yeast ubiquilin mutant (dsk2Δ) is sensitive to Htt103QP overexpression and shows defects in formation of Htt103QP inclusion body, a structure containing protein aggregates. Surprisingly, proteasome-dependent Htt103QP degradation is normal in dsk2Δ mutant, but dsk2Δ mutant showed a defect in the delivery of Htt103QP into vacuoles (lysosomes) in yeast, indicating that ubiquilin proteins facilitate lysosome-dependent clearance of misfolded proteins by promoting inclusion body formation. Our further evidence indicates that the UBL domain of Dsk2 contributes to its functional specificity of ubiquilin/Dsk2. Importantly, the defect of inclusion body formation in in dsk2 mutants is rescued by human ubiquilin 1 or 2, suggesting functional conservation of ubiquilin proteins.