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

 

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 (UPR^ER) which aims to restore proteostasis. During UPR^ER activation, the ER undergoes a process of membrane remodeling, leading to ER membrane expansion, which itself alleviates ER stress (Schuck et al., 2009). The UPR^ER 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 UPR^ER-dependent genes (Almanza et al., 2018). Interestingly, activation of UPR^ER 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 UPR^ER 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 UPR^ER 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 UPR^ER 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 UPR^ER 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 UPR^ER 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 UPR^ER?
• Through which pathway can EHBP-1 exert its role in the metabolic shift and lifespan extension independent of the canonical UPR^ER 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 (UPR^ER) 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 UPR^ER 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.

 

References

• 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

doi: https://doi.org/10.1242/prelights.6866

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