Ubiquilin interacts and enhances the degradation of expanded-polyglutamine proteins

Abstract

Previously we showed that overexpression of ubiquilin reduces protein aggregates and toxicity of expanded polyglutamine proteins. Here, we investigated the mechanism of ubiquilin's protective effect. Immunofluorescence microscopy and immunoprecipitation studies indicated that ubiquilin colocalized and coimmunoprecipitated more with GFP-huntingtin-exon-1-fusion proteins containing a 74-polyglutamine tract than with GFP-huntingtin-fusion proteins containing a 28-polyglutamine tract or with GFP protein alone. Furthermore, overexpression of ubiquilin selectively enhanced the turnover of the expanded GFP-huntingtin-fusion protein. These results suggest that elevating ubiquilin levels could aid in the selective disposal of potentially toxic expanded polyglutamine proteins that are thought to cause several human diseases.

Ubiquitination, localization, and stability of an anti-apoptotic BCL2-like protein, BCL2L10/BCLb, are regulated by Ubiquilin1

“…Ubqln binds ubiquitinated proteins through the UBA, at the same time binding the proteasome through the UBL; it appears to act as a scaffold to facilitate proteasomal degradation of ubiquitinated proteins that have been exported from the ER (24,25). This function could explain most of the proposed functions of Ubqln, such as regulation of autophagy, unfolded protein response, and interaction with both poly-alanine and poly-glutamine expanded proteins (21,22,(27)(28)(29)(30)41). Additional, nonERAD dependent functions for Ubqln, and related proteins, have also been proposed, including a role in the trafficking of amyloid precursor protein and endocytosis of G-protein coupled receptors (18,21,23,26).…”

Current understanding on the pathogenesis of polyglutamine diseases

“…Evidence comes from the findings of mutant protein aggregation and inclusion bodies containing components of the UPS components [75] . An elevation in the ubiquitin level, which enhances the activity of proteasomes, can suppress polyQ toxicity in cells and animal models of HD [76,77] .…”

Recent Developments in Gene Therapy Research Targeted to Cerebellar Disorders

“…As these diseases are caused by the production of toxic polyglutamine proteins (polyQ), a potential therapeutic approach would be to reduce the mutant polyQ by, for example, RNA interference (Xia et al, 2004) or the facilitation of their degradation. The latter may include the enhancement of the ubiquitin-proteasome pathway (Al-Ramahi et al, 2006;Matsumoto et al, 2004;Torashima et al, 2008;Wang & Monteiro, 2007) and autophagy Williams et al, 2006). Autosomal dominant SCA14, characterized by severe cerebellar atrophy and ataxia, is caused by a missense mutation of the PRKCG gene, which encodes the protein kinase C (PKC) gene.…”