A non-canonical arm of UPRER mediates longevity through ER remodeling and lipophagy.

Joseph R Daniele, Ryo Higuchi-Sanabria, Vidhya Ramachandran, Melissa Sanchez, Jenni Durieux, Sarah U Tronnes, Joseph W Paul, Daniel J Esping, Samira Monshietehadi, Melissa G Metcalf, Andrew Dillin

Preprint posted on 15 November 2018

Brain to gut communication shapes lifespan extension in C.elegans: discovery of a non-canonical arm of the UPR ER that leads to metabolic switch and lifespan extension.

Selected by Sandra Franco Iborra

Categories: cell biology


Loss of protein homeostasis is proposed to be one of the “primary hallmarks of ageing” (Lopez-Otin et al., 2013). Indeed, many neurodegenerative diseases, which can be seen as age-related disorders, are characterized by the aggregation of specific proteins, such as α-synuclein in Parkinson’s disease or β-amyloid in Alzheimer’s disease. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) elicits a response called unfolded protein response (UPRER) which aims to restore proteostasis. During UPRER activation, the ER undergoes a process of membrane remodeling, leading to ER membrane expansion, which itself alleviates ER stress (Schuck et al., 2009). The UPRER is mediated by three main signaling branches i) inositol-requiring enzyme 1 (IRE1), ii) protein kinase RNA-like ER kinase (PERK) and iii) activating transcription factor 6 (ATF6). IRE1 activation induces a selective cleavage within the X-box binding protein 1 (XBP1) mRNA to produce a spliced isoform of XBP1, which now can activate the transcription of several UPRER-dependent genes (Almanza et al., 2018). Interestingly, activation of UPRER declines with age (Taylor and Dillin, 2013).

In this preprint, the authors use a model of long-lived C.elegans, which overexpresses the spliced version of xbp1 (xbp-1s) specifically in neurons. Neuronal xbp-1s constitutive expression leads to the specific activation of UPRER in the intestine but not in other tissues (Taylor and Dillin, 2013). The use of neuronal xbp-1s C.elegans enables the study of cell non-autonomous responses upon constitutive UPRER activation in neurons, especially those that lead to lifespan extension.

Key findings

The authors found out that neuronal xbp-1s animals develop transient spherical structures in the intestinal ER termed circular ER-derived membranes (CERMs). CERMs are only seen in these animals at day 4 (early adulthood). Interestingly, CERMs only appear when xbp-1s is overexpressed in neurons, but not when the overexpression takes place in the whole organism or in the intestine, indicating a neuronal non-autonomous mechanism. Moreover, CERM formation and lifespan extension relies on the expression of xbp-1 in intestine.

Neuronal xbp-1s animals show lipid depletion, which is concomitant to decreased lipid droplet content, the primary organelle that stores intestinal lipids in C. elegans. Interestingly, this phenotype is apparent only in early adulthood, at the same time that ER remodeling to create CERMs is found, and depends on xbp-1s expression. This might suggest that ER-remodeling and decreased lipid content act together in the same pathway.

Next, the authors wondered whether ER remodeling and lipid depletion are caused by increased autophagy activity upon UPRER activation. Indeed, neuronal xbp-1s animals have increased intestinal lysosomal content and intestinal CERMs colocalize with autophagy markers. The lower levels of the lipophagy substrate RAB-7 and the presence of ER whorls (ER membranes organized in a regularly spaced, concentric manner) inside the autophagosomes suggests that both lipophagy and ER-phagy are upregulated in the intestinal tissue. Since pharmacological activation of ER stress does not elicit autophagy activation, this might indicate that autophagy-dependent ER remodeling is a phenomenon unique to non-autonomous UPRER signaling.

The complex formed by RAB-10, EHBP-1 and EHD2 proteins has been shown to participate in the engulfment of the lipid droplets by the autophagosome during lipophagy. Deletion of EHBP-1 in neuronal xbp-1s animals suppresses intestinal lipid depletion and lifespan extension without affecting UPRER induction. These results point at EHBP-1 protein as a potential activator of the response leading to lifespan extension.


Overexpression of xbp-1s in neurons induces a remodeling response in intestinal ER, which is concomitant to the depletion of intestinal lipid droplets and necessary for the metabolic switch and lifespan extension in this model.


Future directions and questions for the authors

  • Is there a specific subset of neurons that drive the formation of CERMs in C.elegans? Do different neuronal populations have different sensitivities to UPRER?
  • Through which pathway can EHBP-1 exert its role in the metabolic shift and lifespan extension independent of the canonical UPRER signaling pathway? Does EHBP-1 require the presence of xbp-1 in the intestine for lifespan signaling in C.elegans? Does EHBP-1 participate in lifespan extension in mammalian organisms?
  • The authors described a very specific communication between neurons and intestinal cells in neuronal xbp-1s animals. Which role could the gut-brain axis play in lifespan extension in mammalian organisms?
  • What is the role of lipid degradation in lifespan extension?


Why I like this preprint?

The choice of this preprint might be a little bit biased since I find the research about the mechanisms of ageing fascinating, especially now that there is this open debate on whether we should classify ageing as a disease. In any case, one of the reasons why I chose this preprint was because the authors were investigating a response that is activated upon protein misfolding (UPRER) and there is a clear link between defective protein homeostasis and many neurodegenerative disorders, in which one of the risk factors is ageing. However, it turned out that the authors discovered a non-canonical UPRER mechanism of lifespan extension that might not be as related to protein misfolding as it was previously thought.

The second reason why I particularly like this article is because they analyzed how two separated tissues (neuronal and intestinal tissue) communicate between each other. It’s quite obvious that different tissues in an organism must coordinate but it is not that common to see research that takes into account this tissue communication and coordination. Furthermore, the results shown here might imply that neuronal tissue is more sensible to stress and might be one of the first tissues to communicate it to the rest of the organism.



  • Lopez-Otin C. et al. The hallmarks of aging. 153, 1194-217 (2013).
  • Schuck S. et al. Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response. J Cell Biol. 187, 525-36 (2009).
  • Taylor RC and Dillin A. XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. 153, 1435-47 (2013).

Tags: cell non-autonomous responses, longevity, metabolism

Posted on: 7 January 2019 , updated on: 17 January 2019


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Author's response

The author team shared

An ongoing question in the field of neuronal non-autonomous signaling are what are the neurons involved and what specific signal from these neurons are necessary and/or sufficient for the beneficial effects on non-autonomous UPRER. At the current moment, we can say that dopaminergic neurons are sufficient to elicit the non-autonomous UPRER response. In addition, dopaminergic neurons are necessary for at least some of the beneficial effects found in neuronal non-autonomous UPRER paradigms, but it does not seem to be dopamine itself that elicits this response. Thus, the identification of the neurons – and their signals – involved is quite complex, and is still an ongoing investigation. The question of whether different neuronal populations have different sensitivities to stress is an even more complex question, and is actually a very exciting avenue of research for the lab. For example are dopaminergic neurons more susceptible to ER stress?

As for EHBP-1’s role in metabolic shift and lifespan extension, we do find that knockdown of ehbp-1 is sufficient to completely suppress the CERM formation and lipid depletion found in neuronal xbp-1s overexpressing animals. These data suggest that EHBP-1’s role in CERM formation and/or lipid depletion are responsible for the beneficial effects on lifespan. Moreover, we find that ehbp-1 knockdown does not affect the canonical, chaperone arm of the UPRER. Thus, we can currently separate what we call the canonical (chaperone) arm and non-canonical (lipid metabolism) arms of UPRER, but we have not yet found a way to separate CERM formation from lipid depletion to determine which (or both) are required for the beneficial effects on non-autonomous UPRER. We have already shown that lipid depletion independent of ehbp-1 exists in other long-lived paradigms (cco-1 knockdown and neuronal hsf-1 overexpression), and that some strains with extended lifespan have increased lipid content (daf-2 knockdown). We are currently testing whether ehbp-1 overexpression is sufficient to drive lipid depletion, CERM formation, and/or lifespan extension.

The question of how this relates to mammalian organisms is certainly an important question. While it would seem most obvious to translate the work to the gut-brain axis in mammalian systems, it has already been pretty well understood that the non-autonomous communication between neurons and intestinal cells in C. elegans most closely mirrors the brain-liver communication found in mammalian systems (see doi: 10.1016/j.molcel.2017.05.031. for a review). While it has been previously shown that neuronal XBP-1s overexpression in mice can promote UPR genes and increase lifespan and improve metabolic health, an open question is whether the “non-canonical” arm of UPRER described here, mediating ER remodeling and lipid depletion, happens in the liver of these mice.

Finally, the role of lipid degradation in lifespan extension is a rather heavy area of research that cannot be simply addressed in this author response. It is pretty well-established – in many model systems and even in humans – that during aging, metabolic processes are disrupted and fat accumulation is of concern in multiple tissues, as well as systemically within an organism. Moreover, many lifespan extension paradigms seems to reverse metabolic dysfunction and decrease lipid accumulation, prevent diet-induced obesity, or combat the effects of lipotoxicity. Whether the beneficial effects that we see here with neuronal xbp-1s promoting lipid depletion follows the same paradigm of preventing metabolic dysfunction is still unclear. However, we find that neuronal xbp-1s is not sufficient to prevent lipid accumulation at old age, which does suggest that our paradigm may be different from preventing lipotoxicity at old age.

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