AMP-activated protein kinase-regulated phosphorylation and acetylation of importin α1: Involvement in the nuclear import of RNA-binding protein HuR

Nuclear import of HuR, a shuttling RNA-binding protein, is associated with reduced stability of its target mRNAs. Increased function of the AMP-activated protein kinase (AMPK), an enzyme involved in responding to metabolic stress, was recently shown to reduce the cytoplasmic levels of HuR. Here, we provide evidence that importin α1, an adaptor protein involved in nuclear import, contributes to the nuclear import of HuR through two AMPK-modulated mechanisms. First, AMPK triggered the acetylation of importin α1 on Lys²², a process dependent on the acetylase activity of p300. Second, AMPK phosphorylated importin α1 on Ser¹⁰⁵. Accordingly, expression of importin α1 proteins bearing K22R or S105A mutations failed to mediate the nuclear import of HuR in intact cells. Our results point to importin α1 as a critical downstream target of AMPK and key mediator of AMPK-triggered HuR nuclear import.