Letter | Published:

Transcriptional regulation of autophagy by an FXR–CREB axis

Nature volume 516, pages 108111 (04 December 2014) | Download Citation

Abstract

Lysosomal degradation of cytoplasmic components by autophagy is essential for cellular survival and homeostasis under nutrient-deprived conditions1,2,3,4. Acute regulation of autophagy by nutrient-sensing kinases is well defined3,5,6,7, but longer-term transcriptional regulation is relatively unknown. Here we show that the fed-state sensing nuclear receptor farnesoid X receptor (FXR)8,9 and the fasting transcriptional activator cAMP response element-binding protein (CREB)10,11 coordinately regulate the hepatic autophagy gene network. Pharmacological activation of FXR repressed many autophagy genes and inhibited autophagy even in fasted mice, and feeding-mediated inhibition of macroautophagy was attenuated in FXR-knockout mice. From mouse liver chromatin immunoprecipitation and high-throughput sequencing data12,13,14,15, FXR and CREB binding peaks were detected at 178 and 112 genes, respectively, out of 230 autophagy-related genes, and 78 genes showed shared binding, mostly in their promoter regions. CREB promoted autophagic degradation of lipids, or lipophagy16, under nutrient-deprived conditions, and FXR inhibited this response. Mechanistically, CREB upregulated autophagy genes, including Atg7, Ulk1 and Tfeb, by recruiting the coactivator CRTC2. After feeding or pharmacological activation, FXR trans-repressed these genes by disrupting the functional CREB–CRTC2 complex. This study identifies the new FXR–CREB axis as a key physiological switch regulating autophagy, resulting in sustained nutrient regulation of autophagy during feeding/fasting cycles.

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Acknowledgements

We thank D. Ryerson and D. Tkac for constructing the pGEX4T-FXR clones. We thank M. Montminy for providing Ad-CRTC2 and Ad-CRTC2(S171A), S.-H. Koo for the CREB and CRTC2 plasmids, G. Hotamisligil for Ad-GFP-LC3, and R. Puertollano for the Flag–TFEB plasmid. This study was supported by grants from the National Institutes of Health (DK62777 and DK95842) to J.K.K.

Author information

Author notes

    • Sunmi Seok
    •  & Ting Fu

    These authors contributed equally to this work.

Affiliations

  1. Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA

    • Sunmi Seok
    • , Ting Fu
    • , Sung-E Choi
    • , Subodh Kumar
    • , Byron Kemper
    •  & Jongsook Kim Kemper
  2. Institute for Medical Science, Ajou University School of Medicine, Suwon 442-749, Korea

    • Sung-E Choi
    • , Gyesoon Yoon
    •  & Yup Kang
  3. Department of Bioengineering and the Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA

    • Yang Li
    •  & Jian Ma
  4. Department of Statistics, University of Georgia, Athens, Gerogia 30602, USA

    • Rong Zhu
    • , Xiaoxiao Sun
    •  & Wenxuan Zhong

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Contributions

S.S., T.F. and J.K.K. designed research; S.S., T.F., S.-E.C. and S.K. performed experiments; S.S., T.F., S.-E.C., S.K., G.Y., Y.K., B.K. and J.K.K. analysed data; Y.L., R.Z., X.S., W.Z. and J.M. analysed ChIP-seq genomic data, and S.S., T.F., B.K. and J.K.K. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jongsook Kim Kemper.

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DOI

https://doi.org/10.1038/nature13949

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