The ability to sense metabolic stress is critical for successful cellular adaptation. In eukaryotes, the AMP-activated protein kinase (AMPK), a highly conserved serine/threonine kinase, functions as a critical metabolic sensor. AMPK is activated by the rising ADP/ATP and AMP/ATP ratios during conditions of energy depletion and also by increasing intracellular Ca2+. In response to metabolic stress, AMPK maintains energy homeostasis by phosphorylating and regulating proteins that are involved in many physiological process including glucose and fatty acid metabolism, transcription, cell growth, mitochondrial biogenesis and autophagy. Evidence is mounting that AMPK also plays a role in a number of pathways unrelated to energy metabolism. Here, we identify the recombination activating gene 1 protein (RAG1) as a novel substrate of AMPK. The RAG1/RAG2 complex is a lymphoid-specific endonuclease that catalyzes specific DNA cleavage during V(D)J recombination, which is required for the assembly of the immunoglobulin and T-cell receptor (TCR) genes of the immune system. AMPK directly phosphorylates RAG1 at serine 528, and the phosphorylation enhances the catalytic activity of the RAG complex, resulting in increased cleavage of oligonucleotide substrates in vitro, or recombination of an extrachromosomal substrate in a cellular assay. Our results suggest that V(D)J recombination can be regulated by AMPK activation, providing a potential new link between metabolic stress and development of B and T lymphocytes.

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National Heart, Lung, and Blood Institute
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Maurice, Donald H; Ke, Hengming; Ahmad, Faiyaz et al. (2014) Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov 13:290-314
Um, Jee-Hyun; Brown, Alexandra L; Singh, Samarendra K et al. (2013) Metabolic sensor AMPK directly phosphorylates RAG1 protein and regulates V(D)J recombination. Proc Natl Acad Sci U S A 110:9873-8