Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation.
The mammalian adenosine monophosphate-activated protein kinase (AMPK) is a serine-threonine kinase protein complex that is a central regulator of cellular energy homeostasis. However, the mechanisms by which AMPK mediates cellular responses to metabolic stress remain unclear. We found that AMPK activates transcription through direct association with chromatin and phosphorylation of histone H2B at serine 36. AMPK recruitment and H2B Ser36 phosphorylation colocalized within genes activated by AMPK-dependent pathways, both in promoters and in transcribed regions. Ectopic expression of H2B in which Ser36 was substituted by alanine reduced transcription and RNA polymerase II association to AMPK-dependent genes, and lowered cell survival in response to stress. Our results place AMPK-dependent H2B Ser36 phosphorylation in a direct transcriptional and chromatin regulatory pathway leading to cellular adaptation to stress.
Bungard
David
D
Department of Cellular and Developmental Biology, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA.
Fuerth
Benjamin J
BJ
Zeng
Ping-Yao
PY
Faubert
Brandon
B
Maas
Nancy L
NL
Viollet
Benoit
B
Carling
David
D
Thompson
Craig B
CB
Jones
Russell G
RG
Berger
Shelley L
SL
D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D000222:Adaptation, Physiological; D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002843:Chromatin; D006657:Histones; D016159:Tumor Suppressor Protein p53; D012694:Serine; C534978:Prkaa2 protein, mouse; C526181:PRKAA2 protein, human; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases