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Olfaction regulates organismal proteostasis and longevity via microRNA-dependent signalling

Nature Metabolism volume 1, pages 350–359 (2019)Cite this article

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An Author Correction to this article was published on 03 January 2020

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Abstract

The maintenance of proteostasis is crucial for any organism to survive and reproduce in an ever-changing environment, but its efficiency declines with age1. Post-transcriptional regulators such as micrRNAs (miRNAs) control protein translation of target mRNAs, with major consequences for development, physiology and longevity2,3. Here we show that food odour stimulates organismal proteostasis and promotes longevity in Caenorhabditis elegans through miR-71-mediated inhibition of tir-1 mRNA stability in olfactory AWC neurons. Screening a collection of miRNAs that control ageing3, we found that the miRNA miR-71 regulates lifespan and promotes ubiquitin-dependent protein turnover, particularly in the intestine. We show that miR-71 directly inhibits the Toll-receptor-domain protein TIR-1 in AWC olfactory neurons and that disruption of miR-71–tir-1 or loss of AWC olfactory neurons eliminates the influence of food source on proteostasis. miR-71-mediated regulation of TIR-1 controls chemotactic behaviour and is regulated by odour. Thus, odour perception influences cell-type-specific miRNA–target interaction, thereby regulating organismal proteostasis and longevity. We anticipate that the proposed mechanism of food perception will stimulate further research on neuroendocrine brain-to-gut communication and may open the possibility for therapeutic interventions to improve proteostasis and organismal health via the sense of smell, with potential implications for obesity, diabetes and ageing.

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Fig. 1: Expression of mir-71 in olfactory neurons supports proteostasis and longevity.
Fig. 2: Negative regulation of tir-1 by miR-71 is important for proteostasis and longevity.
Fig. 3: Food-dependent coordination of proteostasis is triggered by miR-71–tir-1 dynamics in AWC neurons.
Fig. 4: Coordination of food perception and organismal proteostasis.

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Data availability

The authors declare that the main data supporting the findings of this study are available within the article and its supplementary information files. RNA sequencing and microarray data have been deposited in the Gene Expression Omibus (GEO) with identifiers GSE124178 (RNA sequencing) and GSE124300 (microarray).

Change history

  • 03 January 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

References

  1. Taylor, R. C. & Dillin, A. Aging as an event of proteostasis collapse. Cold Spring Harb. Perspect. Biol. 3, a004440 (2011).

  2. Krol, J., Loedige, I. & Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nat. Rev. Genet. 11, 597–610 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. de Lencastre, A. et al. MicroRNAs both promote and antagonize longevity in C. elegans. Curr. Biol. 20, 2159–2168 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Mori, M. A. et al. Role of microRNA processing in adipose tissue in stress defense and longevity. Cell Metab. 16, 336–347 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Segref, A., Torres, S. & Hoppe, T. A screenable in vivo assay to study proteostasis networks in Caenorhabditis elegans. Genetics 187, 1235–1240 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Denzel, M. S. et al. Hexosamine pathway metabolites enhance protein quality control and prolong life. Cell 156, 1167–1178 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Ruggiano, A., Foresti, O. & Carvalho, P. Quality control: ER-associated degradation: protein quality control and beyond. J. Cell Biol. 204, 869–879 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Vilchez, D. et al. RPN-6 determines C. elegans longevity under proteotoxic stress conditions. Nature 489, 263–268 (2012).

    Article  CAS  PubMed  Google Scholar 

  9. Calfon, M. et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415, 92–96 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Boulias, K. & Horvitz, H. R. The C. elegans microRNA mir-71 acts in neurons to promote germline-mediated longevity through regulation of DAF-16/FOXO. Cell Metab. 15, 439–450 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hsieh, Y.-W., Chang, C. & Chuang, C.-F. The microRNA mir-71 inhibits calcium signaling by targeting the TIR-1/Sarm1 adaptor protein to control stochastic L/R neuronal asymmetry in C. elegans. PLoS Genet. 8, e1002864 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hobert, O. Terminal selectors of neuronal identity. Curr. Top. Dev. Biol. 116, 455–475 (2016).

    Article  CAS  PubMed  Google Scholar 

  13. Alcedo, J. & Kenyon, C. Regulation of C. elegans longevity by specific gustatory and olfactory neurons. Neuron 41, 45–55 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Troemel, E. R., Kimmel, B. E. & Bargmann, C. I. Reprogramming chemotaxis responses: sensory neurons define olfactory preferences in C. elegans. Cell 91, 161–169 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Jan, C. H., Friedman, R. C., Ruby, J. G. & Bartel, D. P. Formation, regulation and evolution of Caenorhabditis elegans 3′ UTRs. Nature 469, 97–101 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Chuang, C.-F. & Bargmann, C. I. A Toll–interleukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ASK1 MAPKKK signaling. Genes Dev. 19, 270–281 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liberati, N. T. et al. Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response. Proc. Natl Acad. Sci. USA 101, 6593–6598 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xie, Y., Moussaif, M., Choi, S., Xu, L. & Sze, J. Y. RFX transcription factor DAF-19 regulates 5-HT and innate immune responses to pathogenic bacteria in Caenorhabditis elegans. PLoS Genet. 9, e1003324 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Taylor, R. C. & Dillin, A. XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. Cell 153, 1435–1447 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Prahlad, V., Cornelius, T. & Morimoto, R. I. Regulation of the cellular heat shock response in Caenorhabditis elegans by thermosensory neurons. Science 320, 811–814 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Madison, J. M., Nurrish, S. & Kaplan, J. M. UNC-13 interaction with syntaxin is required for synaptic transmission. Curr. Biol. 15, 2236–2242 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Speese, S. et al. UNC-31 (CAPS) Is required for dense-core vesicle but not synaptic vesicle exocytosis in Caenorhabditis elegans. J. Neurosci. 27, 6150–6162 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li, C. The ever-expanding neuropeptide gene families in the nematode Caenorhabditis elegans. Parasitology 131(Suppl.), S109–S127 (2005).

    CAS  PubMed  Google Scholar 

  24. Chalasani, S. H. et al. Dissecting a circuit for olfactory behaviour in Caenorhabditis elegans. Nature 450, 63–70 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Hobert, O. et al. Regulation of interneuron function in the C. elegans thermoregulatory pathway by the ttx-3 LIM homeobox gene. Neuron 19, 345–357 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Bargmann, C. I. Chemosensation in C. elegans. in WormBook (ed. The C. elegans Research Community) https://doi.org/10.1895/wormbook.1.123.1 (2006).

  27. Pokala, N., Liu, Q., Gordus, A. & Bargmann, C. I. Inducible and titratable silencing of Caenorhabditis elegans neurons in vivo with histamine-gated chloride channels. Proc. Natl Acad. Sci. USA 111, 2770–2775 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ward, S. Chemotaxis by the nematode Caenorhabditis elegans: identification of attractants and analysis of the response by use of mutants. Proc. Natl Acad. Sci. USA 70, 817–821 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ben Arous, J., Laffont, S. & Chatenay, D. Molecular and sensory basis of a food related two-state behavior in C. elegans. PLoS One 4, e7584 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Libert, S. et al. Regulation of Drosophila life span by olfaction and food-derived odors. Science 315, 1133–1137 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Maier, W., Adilov, B., Regenass, M. & Alcedo, J. A neuromedin U receptor acts with the sensory system to modulate food type-dependent effects on C. elegans lifespan. PLoS Biol. 8, e1000376 (2010).

  32. Inoue, A. et al. Forgetting in C. elegans is accelerated by neuronal communication via the TIR-1/JNK-1 pathway. Cell Rep. 3, 808–819 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Essuman, K. et al. The SARM1 Toll/interleukin-1 receptor domain possesses intrinsic NAD+ cleavage activity that promotes pathological axonal degeneration. Neuron 93, 1334–1343 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tsvetkov, P. et al. NADH binds and stabilizes the 26S proteasomes independent of ATP. J. Biol. Chem. 289, 11272–11281 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Summers, D. W., Gibson, D. A., DiAntonio, A. & Milbrandt, J. SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation. Proc. Natl Acad. Sci. USA 113, E6271–E6280 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pan, Z.-G. & An, X.-S. SARM1 deletion restrains NAFLD induced by high fat diet (HFD) through reducing inflammation, oxidative stress and lipid accumulation. Biochem. Biophys. Res. Commun. 498, 416–423 (2018).

    Article  CAS  PubMed  Google Scholar 

  37. Lin, C.-W. & Hsueh, Y.-P. Sarm1, a neuronal inflammatory regulator, controls social interaction, associative memory and cognitive flexibility in mice. Brain Behav. Immun. 37, 142–151 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Brooks, K. K., Liang, B. & Watts, J. L. The influence of bacterial diet on fat storage in C. elegans. PLoS One 4, e7545 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Riera, C. E. et al. The sense of smell impacts metabolic health and obesity. Cell Metab. 26, 198–211 (2017).

    Article  CAS  PubMed  Google Scholar 

  40. Teff, K. Nutritional implications of the cephalic-phase reflexes: endocrine responses. Appetite 34, 206–213 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Stiernagle, T. Maintenance of C. elegans.in WormBook (ed. The C. elegans Research Community) https://doi.org/10.1895/wormbook.1.101.1 (2006).

  43. Miedel, M. T. et al. A pro-cathepsin L mutant is a luminal substrate for endoplasmic-reticulum-associated degradation in C. elegans. PLoS One 7, e40145 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Roayaie, K., Crump, J. G., Sagasti, A. & Bargmann, C. I. The Gα protein ODR-3 mediates olfactory and nociceptive function and controls cilium morphogenesis in C. elegans olfactory neurons. Neuron 20, 55–67 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Radman, I., Greiss, S. & Chin, J. W. Efficient and rapid C. elegans transgenesis by bombardment and hygromycin B selection. PLoS One 8, e76019 (2013).

  46. Drexel, T., Mahofsky, K., Latham, R., Zimmer, M. & Cochella, L. Neuron type-specific miRNA represses two broadly expressed genes to modulate an avoidance behavior in C. elegans. Genes Dev. 30, 2042–2047 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Friedland, A. E. et al. Heritable genome editing in C. elegans via a CRISPR–Cas9 system. Nat. Methods 10, 741–743 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Katic, I. & Großhans, H. Targeted heritable mutation and gene conversion by Cas9–CRISPR in Caenorhabditis elegans. Genetics 113, 155754 (2013).

    Google Scholar 

  49. Semple, J. I., Biondini, L. & Lehner, B. Generating transgenic nematodes by bombardment and antibiotic selection. Nat. Methods 9, 118–119 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. Mitchell, D. H., Stiles, J. W., Santelli, J. & Sanadi, D. R. Synchronous growth and aging of Caenorhabditis elegans in the presence of fluorodeoxyuridine 1. J. Gerontol. 34, 28–36 (1979).

  51. Timmons, L. & Fire, A. Specific interference by ingested dsRNA. Nature 395, 854 (1998).

    Article  CAS  PubMed  Google Scholar 

  52. Kamath, R. S., Martinez-Campos, M., Zipperlen, P., Fraser, A. G. & Ahringer, J. Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol. 2, RESEARCH0002 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Rual, J. F. et al. Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. Genome Res. 14, 2162–2168 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jadiya, P. & Nazir, A. A pre- and co-knockdown of RNAseT enzyme, Eri-1, enhances the efficiency of RNAi induced gene silencing in Caenorhabditis elegans. PLoS One 9, e87635 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Hoogewijs, D., Houthoofd, K., Matthijssens, F., Vandesompele, J. & Vanfleteren, J. R. Selection and validation of a set of reliable reference genes for quantitative sod gene expression analysis in C. elegans. BMC Mol. Biol. 9, 9 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Potluri, L. et al. Septal and lateral wall localization of PBP5, the major d,d-carboxypeptidase of Escherichia coli, requires substrate recognition and membrane attachment. Mol. Microbiol. 77, 300–323 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kitazono, T. et al. Multiple signaling pathways coordinately regulate forgetting of olfactory adaptation through control of sensory responses in Caenorhabditis elegans. J. Neurosci. 37, 10240–10251 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Y. Kohara and the Caenorhabditis Genetics Center (funded by the NIH National Center for Research Resources), the Dana-Farber Cancer Institute, Addgene and Geneservice for plasmids, cDNA and strains. We thank A. Segref (University of Cologne, Germany) for sharing unpublished strains and data on brain-to-gut regulation mechanisms. We thank the CECAD Imaging facility for support with confocal microscopy and the Cologne Center for Genomics for microarray analysis and RNA sequencing. This work is supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (CECAD, FKZ: ZUK81/1 and SFB1218) and the European Research Council (ERC-CoG-616499) to T.H. and grants from the Austrian Science Fund (FWF) (W-1207-B09 and SFB-F43–23) and European Research Council (ERC-StG-337161) to L.C.

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Authors and Affiliations

  1. Institute for Genetics and CECAD Research Center, University of Cologne, Cologne, Germany

    Fabian Finger, Franziska Ottens, Alexander Springhorn, Lucie Proksch, Sophia Metz & Thorsten Hoppe

  2. Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria

    Tanja Drexel & Luisa Cochella

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Contributions

F.F., F.O. and A.S. designed, performed and analysed the results of the experiments. A.S. and L.P. performed and analysed the results of the RNA-sequencing experiments; T.D. and L.C. established the gene-edited strains. S.M. performed the stress assays. T.H. supervised the design and data interpretation; F.F., F.O. and T.H. wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Thorsten Hoppe.

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Finger, F., Ottens, F., Springhorn, A. et al. Olfaction regulates organismal proteostasis and longevity via microRNA-dependent signalling. Nat Metab 1, 350–359 (2019). https://doi.org/10.1038/s42255-019-0033-z

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