Fig. 1.

Activation of UPR^ER by overexpression of xbp-1s in CEPsh glia or neurons extends the lifespan of C. elegans. (A) UPR^ER activated by overexpression of xbp-1s in CEPsh glia induces the release of neuropeptides that act on intestinal cells to increase ER stress resistance. These peptides also induce lifespan extension. Indeed, the effect on lifespan and on activation of intestinal UPR^ER of overexpressing spliced xbp-1 (xbp-1s) in CEPsh glia is lost in egl-3 and unc-31 mutant C. elegans (Frakes et al., 2020). While egl-3 encodes a peptidase involved in the processing of neuropeptides, unc-31 is a homolog of CADPS (Ca²⁺-dependent secretion activator) and it is involved in the fusion of dense core vesicles. HSP-4 is the worm homologs of HSPA5, also known as GRP78/BiP, the molecular chaperone for ER stress (Nuss et al., 2008). (B) Overexpressing xbp-1s in intestine activates cell-autonomous UPR^ER but does not affect lifespan (Frakes et al., 2020). (C) UPR^ER activated by overexpressing xbp-1s in neurons induces the release neurotransmitters in a unc-13-dependent manner. unc-13 is the C. elegans homolog of UNC13, a vesicular protein involved in neurotransmitter release. The released neurotransmitters activate the UPR^ER in the intestine, leading to an increase in ER stress resistance in this tissue. The neurotransmitters also lead to lifespan extension (Taylor and Dillin, 2013). (D) Overexpressing xbp-1s in body wall muscle activates cell-autonomous UPR^ER but does not affect lifespan (Taylor and Dillin, 2013).