Direct binding of Ataxin-2 to distinct elements in 3' UTRs promotes mRNA stability and protein expression

Abstract

It has been proposed that Ataxin-2, a member of the like-Sm (LSm) protein family, participates in the regulation of RNA metabolism through interaction with PABPC1. However, the exact biological mechanism and in vivo targets remain unknown. Here, we report that Ataxin-2 binds directly to RNAs in a PABPC1-independent manner. High-throughput sequencing of Ataxin-2-bound RNAs prepared by PAR-CLIP revealed that Ataxin-2 binds predominantly to uridine-rich elements, including well-characterized cis-regulatory AU-rich elements, in the 3' UTRs of target mRNAs. Gene expression analysis after Ataxin-2 depletion or overexpression revealed that Ataxin-2 stabilizes target mRNAs and increases the abundance of the corresponding proteins. A tethering assay demonstrated that Ataxin-2 elicits this effect by direct interaction with mRNAs. We also found that disease-associated polyglutamine expansion downregulates the physiological activity of Ataxin-2. These findings suggest that Ataxin-2 is an RNA-binding protein that targets cis-regulatory elements in 3' UTRs to stabilize a subset of mRNAs and increase protein expression.