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MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability

Nature Cell Biology volume 15, pages 668–676 (2013)Cite this article

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A Corrigendum to this article was published on 23 December 2014

This article has been updated

Abstract

Fat is stored or mobilized according to food availability. Malfunction of the mechanisms that ensure this coordination underlie metabolic diseases in humans. In mammals, lysosomal and autophagic function is required for normal fat storage and mobilization in the presence or absence of food. Autophagy is tightly linked to nutrients. However, if and how lysosomal lipolysis is coupled to nutritional status remains to be determined. Here we identify MXL-3 and HLH-30 (TFEB orthologue) as transcriptional switches coupling lysosomal lipolysis and autophagy to nutrient availability and controlling fat storage and ageing in Caenorhabditis elegans. Transcriptional coupling of lysosomal lipolysis and autophagy to nutrients is also observed in mammals. Thus, MXL-3 and HLH-30 orchestrate an adaptive and conserved cellular response to nutritional status and regulate lifespan.

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Figure 1: lipl-1 to 5 are upregulated following fasting.
Figure 2: LIPL-mediated lysosomal lipolysis controls lipid-droplet fat stores.
Figure 3: MXL-3 represses lysosomal lipolysis in ad libitum-fed conditions.
Figure 4: HLH-30 induces lysosomal lipolysis following fasting.
Figure 5: HLH-30 activates vital cellular responses to starvation.
Figure 6: Lysosomal lipolysis and autophagy are transcriptionally linked to nutrients in mammals.
Figure 7: Lysosomal lipolysis delays C. elegans ageing.
Figure 8: MXL-3 and HLH-30 model of action.

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Change history

  • 21 November 2014

    The original version of this Article did not mention TFEB, the mammalian orthologue of the protein HLH-30, in the abstract. The fourth sentence in the abstract should have read 'Here we identify MXL-3 and HLH-30 (TFEB orthologue) as transcriptional switches coupling lysosomal lipolysis and autophagy to nutrient availability and controlling fat storage and ageing in Caenorhabditis elegans.' This has been corrected in all online versions of the Article.

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Acknowledgements

We thank members of the Ruvkun, Ausubel and Kaplan laboratories for helpful comments, especially S. Curran, A. Lee-Conery and M. Wang for help with longevity experiments, J. Larkins-Ford for carrying out Biosort analyses, J. Xu for help with qRT–PCR experiments, J. Bai for acquiring confocal microscopy images, and J. Melo, C. Danna and A. Frand for helpful reading of the manuscript. We are grateful to R. Niedra, B. Seed, Y. Namiki and M. Oettinger for sharing expertise and reagents for mammalian experiments, and thanks H. Y. Mak, A. Soukas, M. Van Gilst, M. Freeman, A. Saghatelian and A. Tyler for protocols, access to equipment and discussions on lipid measurements. We are also grateful to A. Mah and D. Baillie for generating some transgenic strains used early in this project but not presented here, and thank N. Martinez and M. Walhout for sharing reagents and expertise on yeast one-hybrid experiments. We would like to thank the National Bioresource Project, the C. elegans Genetics Center, C. Bargmann and G. Hermann for strains. E.J.O’R. was a recipient of a Human Frontiers Science Program Postdoctoral fellowship. This work was supported by grants R01DK070147 to G.R. and K99DK087928 to E.J.O’R.

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Authors and Affiliations

  1. Department of Molecular Biology, Massachusetts General Hospital, 02114, USA

    Eyleen J. O’Rourke & Gary Ruvkun

  2. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA

    Eyleen J. O’Rourke & Gary Ruvkun

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  1. Eyleen J. O’Rourke
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Contributions

E.J.O’R. designed the overall studies, carried out the experiments and wrote the manuscript. G.R. discussed results and revised the manuscript.

Corresponding authors

Correspondence to Eyleen J. O’Rourke or Gary Ruvkun.

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The authors declare no competing financial interests.

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O’Rourke, E., Ruvkun, G. MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability. Nat Cell Biol 15, 668–676 (2013). https://doi.org/10.1038/ncb2741

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