title: Ubiquilin/Dsk2 promotes inclusion body formation and vacuole (lysosome)-mediated disposal of mutated huntingtin.
abstract: Ubiquilin proteins contain a ubiquitin-like domain (UBL) and ubiquitin-associated domain(s) that interact with the proteasome and ubiquitinated substrates, respectively. Previous work established the link between ubiquilin mutations and neurodegenerative diseases, but the function of ubiquilin proteins remains elusive. Here we used a misfolded huntingtin exon I containing a 103-polyglutamine expansion (Htt103QP) as a model substrate for the functional study of ubiquilin proteins. We found that yeast ubiquilin mutant (dsk2Δ) is sensitive to Htt103QP overexpression and has a defect in the formation of Htt103QP inclusion bodies. Our evidence further suggests that the UBL domain of Dsk2 is critical for inclusion body formation. Of interest, Dsk2 is dispensable for Htt103QP degradation when Htt103QP is induced for a short time before noticeable inclusion body formation. However, when the inclusion body forms after a long Htt103QP induction, Dsk2 is required for efficient Htt103QP clearance, as well as for autophagy-dependent delivery of Htt103QP into vacuoles (lysosomes). Therefore our data indicate that Dsk2 facilitates vacuole-mediated clearance of misfolded proteins by promoting inclusion body formation. Of importance, the defect of inclusion body formation in dsk2 mutants can be rescued by human ubiquilin 1 or 2, suggesting functional conservation of ubiquilin proteins.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306-4300.
authors.forename: Kun-Han
authors.initials: KH
authors.lastname: Chuang
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306-4300.
authors.forename: Fengshan
authors.initials: F
authors.lastname: Liang
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306-4300.
authors.forename: Ryan
authors.initials: R
authors.lastname: Higgins
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306-4300 yanchang.wang@med.fsu.edu.
authors.forename: Yanchang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D001343:Autophagy; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002479:Inclusion Bodies / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination; D014452:Ubiquitins / Q000235:genetics* / Q000378:metabolism*; D014617:Vacuoles / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C100415:DSK2 protein, S cerevisiae; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; D014452:Ubiquitins; D046988:Proteasome Endopeptidase Complex