한빛사 논문
Abstract
Hi-Jai R. Shin1*, Hyunkyung Kim1*, Sungryong Oh1, Jun-Gi Lee1, Minjung Kee1, Hyun-Jeong Ko2, Mi-Na Kweon3, Kyoung-Jae Won4 & Sung Hee Baek1
1Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul, South Korea. 2Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea. 3Mucosal Immunology Laboratory, Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea. 4The Institute for Diabetes, Obesity, and Metabolism, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
* These authors contributed equally to this work.
Correspondence and requests for materials should be addressed to S.H.B.
Autophagy is a highly conserved self-digestion process, which is essential for maintaining homeostasis and viability in response to nutrient starvation1, 2, 3, 4. Although the components of autophagy in the cytoplasm have been well studied5, 6, 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.
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