Phosphorylation of p40^AUF1 regulates binding to A + U-rich mRNA-destabilizing elements and protein-induced changes in ribonucleoprotein structure

Messenger RNA turnover directed by A + U-rich elements (AREs) involves selected ARE-binding proteins. Whereas several signaling systems may modulate ARE-directed mRNA decay and/or post-translationally modify specific trans-acting factors, it is unclear how these mechanisms are linked. In THP-1 monocytic leukemia cells, phorbol ester-induced stabilization of some mRNAs containing AREs was accompanied by dephosphorylation of Ser⁸³ and Ser⁸⁷ of polysome-associated p40^AUF1. Here, we report that phosphorylation of p40^AUF1 influences its ARE-binding affinity as well as the RNA conformational dynamics and global structure of the p40 ^AUF1-ARE ribonucleoprotein complex. Most notably, association of unphosphorylated p40^AUF1 induces a condensed RNA conformation upon ARE substrates. By contrast, phosphorylation of p40^AUF1 at Ser ⁸³ and Ser⁸⁷ inhibits this RNA structural transition. These data indicate that selective AUF1 phosphorylation may regulate ARE-directed mRNA turnover by remodeling local RNA structures, thus potentially altering the presentation of RNA and/or protein determinants involved in subsequent trans-factor recruitment.