Article | Published:

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

Nature Cell Biology volume 15, pages 668676 (2013) | Download Citation


  • A Corrigendum to this article was published on 23 December 2014

This article has been updated


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1.

    A note on the absorption of fat. Am. J. Physiol. 24, 294–296 (1909).

  2. 2.

    et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).

  3. 3.

    & Lipases in lysosomes, what for? Autophagy 5, 866–867 (2009).

  4. 4.

    , , & Potential role of autophagy in modulation of lipid metabolism. Am. J. Physiol. Endocrinol. Metab. 298, E1–E7 (2010).

  5. 5.

    & Global analysis of dauer gene expression in Caenorhabditis elegans. Development 130, 1621–1634 (2003).

  6. 6.

    , , , & Nutrient control of gene expression in Drosophila: microarray analysis of starvation and sugar-dependent response. EMBO J. 21, 6162–6173 (2002).

  7. 7.

    et al. Starvation response in mouse liver shows strong correlation with life-span-prolonging processes. Physiol. Genom. 17, 230–244 (2004).

  8. 8.

    et al. Inducible antibacterial defense system in C. elegans. Curr. Biol. 12, 1209–1214 (2002).

  9. 9.

    pTARGET: a web server for predicting protein subcellular localization. Nucleic Acids Res. 34, W210–W213 (2006).

  10. 10.

    & pTARGET [corrected] a new method for predicting protein subcellular localization in eukaryotes. Bioinformatics 21, 3963–3969 (2005).

  11. 11.

    et al. Function of the Caenorhabditis elegans ABC transporter PGP-2 in the biogenesis of a lysosome-related fat storage organelle. Mol. Biol. Cell 18, 995–1008 (2007).

  12. 12.

    et al. A multiparameter network reveals extensive divergence between C. elegans bHLH transcription factors. Cell 138, 314–327 (2009).

  13. 13.

    , , & C. elegans major fats are stored in vesicles distinct from lysosome-related organelles. Cell Metab. 10, 430–435 (2009).

  14. 14.

    et al. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421, 268–272 (2003).

  15. 15.

    et al. A gene network regulating lysosomal biogenesis and function. Science 325, 473–477 (2009).

  16. 16.

    et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429–1433 (2011).

  17. 17.

    & Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 43, 67–93 (2009).

  18. 18.

    , & Gene activities that mediate increased life span of C. elegans insulin-like signaling mutants. Genes Dev. 21, 2976–2994 (2007).

  19. 19.

    et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 1387–1391 (2003).

  20. 20.

    et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet 4, e24 (2008).

  21. 21.

    & Caenorhabditis elegans dauers need LKB1/AMPK to ration lipid reserves and ensure long-term survival. Nature 457, 210–214 (2009).

  22. 22.

    , , , & IRE-1 and HSP-4 contribute to energy homeostasis via fasting-induced lipases in C. elegans. Cell Metab. 9, 440–448 (2009).

  23. 23.

    , , & Insulin/IGF-1 receptor signaling enhances biosynthetic activity and fat mobilization in the initial phase of starvation in adult male C. elegans. Cell Metab. 14, 390–402 (2011).

  24. 24.

    , & A Caenorhabditis elegans nutrient response system partially dependent on nuclear receptor NHR-49. Proc. Natl Acad. Sci. USA 102, 13496–13501 (2005).

  25. 25.

    et al. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev. 24, 1403–1417 (2010).

  26. 26.

    et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31, 1095–1108 (2012).

  27. 27.

    et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal 5, ra42 (2012).

  28. 28.

    A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45 (2001).

  29. 29.

    , , & pWormgatePro enables promoter-driven knockdown by hairpin RNA interference of muscle and neuronal gene products in Caenorhabditis elegans. Invert Neurosci. 6, 5–12 (2006).

  30. 30.

    & Genetic dissection of polyunsaturated fatty acid synthesis in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 99, 5854–5859 (2002).

  31. 31.

    , , & A gateway-compatible yeast one-hybrid system. Genome Res. 14, 2093–2101 (2004).

  32. 32.

    , , & Chromatin immunoprecipitation (ChIP) coupled to detection by quantitative real-time PCR to study transcription factor binding to DNA in Caenorhabditis elegans. Nat. Protoc. 3, 698–709 (2008).

  33. 33.

    , , , & LAAT-1 is the lysosomal lysine/arginine transporter that maintains amino acid homeostasis. Science 337, 351–354 (2012).

Download references


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.

Author information


  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


  1. Search for Eyleen J. O’Rourke in:

  2. Search for Gary Ruvkun in:


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

Competing interests

The authors declare no competing financial interests.

Corresponding authors

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

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary Information

Excel files

  1. 1.

    Supplementary Information

    Supplementary Table 1

  2. 2.

    Supplementary Information

    Supplementary Table 2

  3. 3.

    Supplementary Information

    Supplementary Table 3

  4. 4.

    Supplementary Information

    Supplementary Table 4

  5. 5.

    Supplementary Information

    Supplementary Table 5

  6. 6.

    Supplementary Information

    Supplementary Table 6

  7. 7.

    Supplementary Information

    Supplementary Table 7

  8. 8.

    Supplementary Information

    Supplementary Table 8

  9. 9.

    Supplementary Information

    Supplementary Table 9

  10. 10.

    Supplementary Information

    Supplementary Table 10

About this article

Publication history





Further reading Further reading