Letter | Published:

AMPK–SKP2–CARM1 signalling cascade in transcriptional regulation of autophagy

Nature volume 534, pages 553557 (23 June 2016) | Download Citation

Abstract

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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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

The RNA-seq and H3R17me2 ChIP–seq data sets have been deposited in the NCBI Gene Expression Omnibus (GEO) database under the accession number GSE72901.

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Acknowledgements

We thank members of the Chromatin Dynamics Research Center for technical assistance and discussions and J. Kim and J. Chung for valuable reagents and discussions. We thank Y. S. Yu for illustrations. The TEM data were analysed in the Korean Basic Science Institute. Carm1 knockout and knock-in MEFs were provided by M. T. Bedford. Ampk DKO MEFs was a gift from B. Viollet, and Foxo1.3.4f/f MEFs were a gift from R. DePinho and J.-H. Paik. This work was supported by Creative Research Initiatives Program (Research Center for Chromatin Dynamics, 2009-0081563) to S.H.B.; the National Junior Research Fellowship (NRF-2011-A01496-0001806) to H.-J.R.S.; the Basic Science Research Program (NRF-2014R1A6A3A0405 7910) to H.K. from the National Research Foundation (NRF) grant funded by the South Korean government (MSIP); NIH grant (R01DK106027) to K.-J.W.

Author information

Author notes

    • Hi-Jai R. Shin
    •  & Hyunkyung Kim

    These authors contributed equally to this work.

Affiliations

  1. Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul, South Korea

    • Hi-Jai R. Shin
    • , Hyunkyung Kim
    • , Sungryong Oh
    • , Jun-Gi Lee
    • , Minjung Kee
    •  & Sung Hee Baek
  2. Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea

    • Hyun-Jeong Ko
  3. Mucosal Immunology Laboratory, Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea

    • Mi-Na Kweon
  4. The Institute for Diabetes, Obesity, and Metabolism, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Kyoung-Jae Won

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Contributions

H.-J.R.S., H.K., S.O., J.-G.L. and M.K. performed the cell biology and biochemistry experiments; H.-J.K. and M.-N.K. provided TEM analysis and critical comments; H.-J.R.S. and K.J.W. performed RNA and ChIP–seq preparation and systemic analysis; H.-J.R.S., H.K., K.J.W. and S.H.B. organized and analysed the data; H.-J.R.S., K.J.W. and S.H.B. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sung Hee Baek.

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    Supplementary Information

    This file contains Supplementary Figure 1 showing the original immunoblot images and Supplementary Tables 1-3.

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DOI

https://doi.org/10.1038/nature18014

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