AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy.
Autophagy is a highly conserved self-digestion process, which is essential for maintaining homeostasis and viability in response to nutrient starvation. Although the components of autophagy in the cytoplasm have been well studied, the molecular basis for the transcriptional and epigenetic regulation of autophagy is poorly understood. Here we identify co-activator-associated arginine methyltransferase 1 (CARM1) as a crucial component of autophagy in mammals. Notably, CARM1 stability is regulated by the SKP2-containing SCF (SKP1-cullin1-F-box protein) E3 ubiquitin ligase in the nucleus, but not in the cytoplasm, under nutrient-rich conditions. Furthermore, we show that nutrient starvation results in AMP-activated protein kinase (AMPK)-dependent phosphorylation of FOXO3a in the nucleus, which in turn transcriptionally represses SKP2. This repression leads to increased levels of CARM1 protein and subsequent increases in histone H3 Arg17 dimethylation. Genome-wide analyses reveal that CARM1 exerts transcriptional co-activator function on autophagy-related and lysosomal genes through transcription factor EB (TFEB). Our findings demonstrate that CARM1-dependent histone arginine methylation is a crucial nuclear event in autophagy, and identify a new signalling axis of AMPK-SKP2-CARM1 in the regulation of autophagy induction after nutrient starvation.
Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul, South Korea.
Hi-Jai R
HJ
Shin
Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul, South Korea.
Hyunkyung
H
Kim
Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul, South Korea.
Sungryong
S
Oh
Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul, South Korea.
Jun-Gi
JG
Lee
Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul, South Korea.
Minjung
M
Kee
Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.
Hyun-Jeong
HJ
Ko
Mucosal Immunology Laboratory, Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Mi-Na
MN
Kweon
The Institute for Diabetes, Obesity, and Metabolism, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Kyoung-Jae
KJ
Won
Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul, South Korea.
Sung Hee
SH
Baek
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005508:Food Deprivation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000235:genetics; D008745:Methylation; D051379:Mice; D010766:Phosphorylation; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D006657:Histones; D044786:S-Phase Kinase-Associated Proteins; C484068:Tcfeb protein, mouse; D001120:Arginine; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D044843:SKP Cullin F-Box Protein Ligases; D055372:AMP-Activated Protein Kinases