Olfactory chemosensation extends lifespan through TGF-β signaling and UPR activation
Posted on: 5 December 2022 , updated on: 1 September 2023
Preprint posted on 13 October 2022
Article now published in Nature Aging at http://dx.doi.org/10.1038/s43587-023-00467-1
Danger ahead – trust your gut feeling! Metabolites from pathogenic bacteria triggers a stress response in the worm’s gut.
Selected by Chee Kiang EweCategories: animal behavior and cognition, genetics, neuroscience
Updated 1 September 2023 with a postLight by Chee Kiang Ewe
This work was recently published in Nature Aging. It has been great to follow the journey of this paper from preprint to published article. Notably, the key conclusions presented in the revised paper largely mirror those from the preprint. The preprint demonstrated that TGFβ signaling is required for the cell non-autonomous UPRER activation in response to pathogen perception as knocking out daf-7 or daf-1 inhibits 1-undecene-induced UPRER activation.
In the revised paper, the authors provide additional support to the claim by rescuing daf-1 expression specifically in the RIM/RIC interneurons, which recovers UPRER activation in daf-1(-) mutant. Furthermore, the authors found that ablating ASI using a split caspase system effectively blocks 1-undecene-induced UPRER activation.
The original preprint reported that exposure to 1-undecene extends the animals’ lifespan through the activation of the UPRER. The revised article goes even further by demonstrating that this lifespan extension induced by 1-undecene depends on daf-7 and daf-1.
These new findings significantly substantiate the claim that the ASI-RIM/RIC neuronal circuit mediated by TGFβ signaling regulates 1-undecene-induced UPRER activation. This paper elegantly demonstrates how sensing bacterial metabolites can enhance the worms’ immune defense which may in turn promoting their survival. Congratulations to all the authors involved in this beautiful study!
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
doi: https://doi.org/10.1242/prelights.33242
Read preprintSign up to customise the site to your preferences and to receive alerts
Register hereAlso in the animal behavior and cognition category:
Neural Basis of Number Sense in Larval Zebrafish
Muhammed Sinan Malik
Pharyngeal neuronal mechanisms governing sour taste perception in Drosophila melanogaster
Matthew Davies
Precision Farming in Aquaculture: Use of a non-invasive, AI-powered real-time automated behavioural monitoring approach to predict gill health and improve welfare in Atlantic salmon (Salmo salar) aquaculture farms
Jasmine Talevi
Also in the genetics category:
Intracellular diffusion in the cytoplasm increases with cell size in fission yeast
Leeba Ann Chacko, Sameer Thukral
HIF1A contributes to the survival of aneuploid and mosaic pre-implantation embryos
Anchel De Jaime Soguero
Significantly reduced, but balanced, rates of mitochondrial fission and fusion are sufficient to maintain the integrity of yeast mitochondrial DNA
Leeba Ann Chacko
Also in the neuroscience category:
Neural Basis of Number Sense in Larval Zebrafish
Muhammed Sinan Malik
Alzheimer’s Disease Patient Brain Extracts Induce Multiple Pathologies in Vascularized Neuroimmune Organoids for Disease Modeling and Drug Discovery
Manuel Lessi
Deciphering the nanoscale architecture of presynaptic actin using a micropatterned presynapse-on-glass model
Felipe Del Valle Batalla
preListsanimal behavior and cognition category:
in the9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
List by | Martin Estermann |
Bats
A list of preprints dealing with the ecology, evolution and behavior of bats
List by | Baheerathan Murugavel |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
List by | Ana Dorrego-Rivas |
Also in the genetics category:
BSDB/GenSoc Spring Meeting 2024
A list of preprints highlighted at the British Society for Developmental Biology and Genetics Society joint Spring meeting 2024 at Warwick, UK.
List by | Joyce Yu, Katherine Brown |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
List by | Reinier Prosee |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
List by | Sergio Menchero et al. |
Semmelweis Symposium 2022: 40th anniversary of international medical education at Semmelweis University
This preList contains preprints discussed during the 'Semmelweis Symposium 2022' (7-9 November), organised around the 40th anniversary of international medical education at Semmelweis University covering a wide range of topics.
List by | Nándor Lipták |
20th “Genetics Workshops in Hungary”, Szeged (25th, September)
In this annual conference, Hungarian geneticists, biochemists and biotechnologists presented their works. Link: http://group.szbk.u-szeged.hu/minikonf/archive/prg2021.pdf
List by | Nándor Lipták |
2nd Conference of the Visegrád Group Society for Developmental Biology
Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)
List by | Nándor Lipták |
EMBL Conference: From functional genomics to systems biology
Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020
List by | Jesus Victorino |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
List by | Maiko Kitaoka et al. |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
List by | Hiral Shah |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
List by | Sandra Malmgren Hill |
Zebrafish immunology
A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.
List by | Shikha Nayar |
Also in the neuroscience category:
2024 Hypothalamus GRC
This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.
List by | Nathalie Krauth |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
List by | Alex Eve, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
List by | Helen Zenner |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
List by | Ana Dorrego-Rivas |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
List by | Madhuja Samaddar et al. |
SDB 78th Annual Meeting 2019
A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.
List by | Alex Eve |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
List by | Sandra Malmgren Hill |
Young Embryologist Network Conference 2019
Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London
List by | Alex Eve |