AMPK alpha 2 translocates into the nucleus and interacts with hnRNP H: Implications in metformin-mediated glucose uptake

Abstract

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a cytoplasmic protein that plays a critical role in the maintenance of energy homeostasis. However, its role in the nucleus is still largely unknown. Here, we showed that AMPK alpha 2 translocated into the nucleus during muscle differentiation. We also showed that upon treatment with 5-aminoimidazole-4-carboxy-amide-1-D-ribofuranoside (AICAR), an AMPK activator, AMPK rapidly translocated into the nucleus in rat myoblast L6 cells. On the other hand, the AMPK alpha 2 phosphorylation-defective mutant did not translocate into the nucleus. Knockdown of AMPK alpha 2 suppressed the differentiation-induced expression of myogenin, a differentiation marker. A physiological AMPK activator, metformin, also induced the translocation of AMPK alpha 2 into the nucleus. Both inhibition and knockdown of AMPK alpha 2 suppressed metformin-mediated glucose uptake. In addition, AMPK alpha 2 was shown to directly interact with the heterogeneous nuclear ribonucleoprotein H (hnRNP H). AICAR treatment increased the phosphorylation of hnRNP H. Metformin increased the interaction between AMPK alpha 2 and hnRNP H in the nucleus. Knockdown of hnRNP H blocked metformin-induced glucose uptake. In summary, these results demonstrate that AMPK alpha 2 translocates into the nucleus via phosphorylation, AMPK alpha 2 interacts with and phosphorylates hnRNP H in the nucleus, and such a protein-protein interaction modulates metformin-mediated glucose uptake. (C) 2014 Elsevier Inc. All rights reserved.