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Olfactory chemosensation extends lifespan through TGF-β signaling and UPR activation

Evandro A. De-Souza, Maximillian A. Thompson, Rebecca C. Taylor

Preprint posted on 13 October 2022 https://www.biorxiv.org/content/10.1101/2022.10.12.511902v2

Danger ahead – trust your gut feeling! Metabolites from pathogenic bacteria triggers a stress response in the worm’s gut.

Selected by Chee Kiang Ewe

Background:

Stress-induced accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers the conserved unfolded protein response (UPRER), a complex signaling network that promotes proteostasis (or triggers cell death if the ER damage is irreversible) (Todd et al., 2008). In the nematode C. elegans, UPRER is required for the innate immune response to microbes (Richardson et al., 2010). In this exciting preprint, the researchers found that the perception of a specific pathogen-associated odorant molecule activates cell non-autonomous UPRER as a defense mechanism. As well, they could show that lifespan and proteostasis can be modulated by sensory inputs. This study, therefore, provides an intriguing connection between sensory perception, cellular stress response, and longevity.

Major findings:

1) Bacterial odorants activate UPRER in the intestine

To investigate whether pathogen-associated odors may trigger a stress response in C. elegans, the authors exposed the animals to various odorants secreted by pathogenic microbes, including Pseudomonas aeruginosa and Staphylococcus aureus, and monitored the expression of hsp-4 (which encodes the homolog of BiP, a conversed sensor of UPRER). They found that exposure to 1-undecene, 2-nonanone, and pyrrole strongly upregulated hsp-4 in the intestine.

ER stress leads to the activation of IRE-1 which cleaves the mRNA encoding the bZIP transcription factor XBP-1 into its active form, XBP-1s, which subsequently controls a wide range of targets that mediate ER proteostasis. The authors report that knocking out ire-1 or xbp-1 blocked 1-undecene-induced hsp-4 upregulation, and that the expression of xbp-1s was increased in the intestine in the presence of 1-undecene, suggesting that olfactory input may trigger cell non-autonomous UPRER (Figure 1).

2) 1-undecene exposure induces TGFβ signaling in ASI chemosensory neurons

To further investigate how neuronal signals mediate inter-tissue UPRER in response to 1-undecene, the authors eliminated UNC-13, a presynaptic protein required for synaptic vesicle exocytosis, and found that 1-undecene failed to induce UPRER in these mutant worms. In addition, the authors showed that daf-7 (which encodes a TGFβ homolog) was upregulated in ASI chemosensory neurons upon 1-undecene exposure. Moreover, worms lacking daf-7 or daf-1 (encoding a DAF-7 receptor expressed in RIM/RIC interneurons) failed to respond to 1-undecene, indicating that the activation of TGFβ signaling in the nervous system triggers cell non-autonomous UPRER (Figure 1).

3) 1-undecene exposure promotes longevity and proteostasis

Interestingly, the authors found that 1-undecene exposure prolongs the lifespan of worms. This effect was abrogated in the absence of xbp-1, demonstrating the requirement of UPRER activation. In addition, the authors could demonstrate that worms exposed to 1-undecene show reduced expression of YFP-tagged polyglutamine (polyQ) repeats, suggesting enhanced proteostasis in 1-undecene-treated worms (Figure 1).

Figure 1: 1-undecene exposure leads to TGF-β signaling in sensory neurons and inter-tissue regulation of UPRER. Adapted from De-Souza, Thompson, Taylor (2022).

What I liked about this preprint:

This preprint convincingly demonstrates how neuronal perception of odorants may elicit a cellular stress response in peripheral tissue. This indicates that sensing bacterial metabolites may prime the worms’ immune defense – an adaptive strategy that promotes survival. As well, this and other previous studies demonstrate the regulation of longevity pathway by sensory inputs, providing an exciting avenue to manipulate lifespan in animals. Overall, the genetic experiments in this preprint were exhaustive and the conclusions were nicely supported by the results.

Questions for the authors:

Do you know how RIM/RIC communicates with the intestine? It would be interesting to see if 1-undecene could prime the worms for future infection and increase survival during infection.

References:

Richardson, C. E., Kooistra, T., & Kim, D. H. (2010). An Essential Role for XBP-1 in Host Protection against Immune Activation in C. elegans. Nature, 463(7284), 1092. https://doi.org/10.1038/NATURE08762

Todd, D. J., Lee, A. H., & Glimcher, L. H. (2008). The endoplasmic reticulum stress response in immunity and autoimmunity. Nature Reviews Immunology 2008 8:9, 8(9), 663–674. https://doi.org/10.1038/nri2359

Tags: neuronal perception, tgf beta, upr

Posted on: 5 December 2022

doi: https://doi.org/10.1242/prelights.33242

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Author's response

Maximilian A Thompson shared

Do you know how RIM/RIC communicates with the intestine?

We have shown in an earlier study that tyramine synthesis by the RIM/RIC interneurons mediates communication of UPR activation to the intestine (PMID: 33232669). Interestingly, though, tyramine synthesis does not seem to be required for UPR activation by 1-undecene. We are currently interested in determining whether RIM/RIC neurons really are needed for 1-undecene-mediated UPR activation in intestinal cells, and if so, how they do this in the context of chemosensory stimulation.

It would be interesting to see if 1-undecene could prime the worms for future infection and increase survival during infection.

In fact, we know that 1-undecene can do just that, as shown by Varsha Singh’s lab in 2021 (PMID: 34086368). Their work focused on the activation of the immune response by 1-undecene. However, we have found that the activation of the UPR which we see is not downstream of the immune pathways that were shown to be activated in the Singh lab study, and we think this UPR activation is probably happening in parallel to the immune response. So it seems that you can achieve a hormesis-like boost to the UPR by basically tricking the worm into reacting to stress which never arrives, rather than subjecting it to actual stress. It would be really interesting to see if this logic extends to other stresses.

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