SUMO-1 promotes degradation of the polyglutamine disease protein ataxin-3

Polyglutamine (polyQ) diseases are caused by the expansion of polyQ repeats in the respective gene products. Intracellular accumulation of disease proteins is a hallmark of polyQ diseases; however, whether the increased aggregation of polyQ protein is the cause of diseases is still controversial. Efforts have been made to clarify the relationship between protein aggregation and pathogenesis of polyQ diseases. Especially, the roles of post-translational modifications garner attention because of their roles in regulating protein stability and aggregation. Small ubiquitin-like modifiers (SUMO) covalently attach to target proteins and affect the diverse cellular processes. PolyQ proteins such as huntingtin and ataxin-1 are covalently modified by SUMO-1 and consequently accumulate in the insoluble fraction. To study the effects of SUMO-1 on the polyQ protein ataxin-3, we examined SUMO-1 modification of ataxin-3 and tested if SUMOylation modulates ataxin-3 aggregation. Surprisingly, ataxin-3 was not covalently modified by SUMO-1; instead, SUMO-1 interacted with ataxin-3 mostly in nucleus and as a result reduced the cellular level of ataxin-3. MG132 treatment blocked the effect of SUMO-1 suggesting that SUMO-induced degradation of ataxin-3 is mediated by ubiquitinproteasome system. Chase experiment confirmed that such effects were indeed due to the increased degradation of ataxin-3 by SUMO-1. While the aggregation of ataxin-3 was not affected by SUMO-1, the presence of polyQ-expanded ataxin-3 increased the recruitment of SUMO-1 into nuclear bodies. These results together suggest that SUMO-1 contributes to the regulation of the cellular level of ataxin-3 protein by facilitating the degradation process.