Neuronal XBP-1 Activates Intestinal Lysosomes to Improve Proteostasis in C. elegans

The unfolded protein response of the endoplasmic reticulum (UPRER) is a crucial mediator of secretory pathway homeostasis. Expression of the spliced and active form of the UPRER transcription factor XBP-1, XBP-1s, in the nervous system triggers activation of the UPRER in the intestine of Caenorhabditis elegans (C. elegans) through release of a secreted signal, leading to increased longevity. We find that expression of XBP-1s in the neurons or intestine of the worm strikingly improves proteostasis in multiple tissues, through increased clearance of toxic proteins. To identify the mechanisms behind this enhanced proteostasis, we conducted intestine-specific RNA-seq analysis to identify genes upregulated in the intestine when XBP-1s is expressed in neurons. This revealed that neuronal XBP-1s increases the expression of genes involved in lysosome function. Lysosomes in the intestine of animals expressing neuronal XBP-1s are more acidic, and lysosomal protease activity is higher. Moreover, intestinal lysosome function is necessary for enhanced lifespan and proteostasis. These findings suggest that activation of the UPRER in the intestine through neuronal signaling can increase the activity of lysosomes, leading to extended longevity and improved proteostasis across tissues. [Display omitted] •Xbp-1s expressed in the neurons or intestine of C. elegans improves proteostasis•Neuronal xbp-1s drives expression of lysosomal genes in the intestine•Intestinal lysosomes show enhanced acidity and activity upon xbp-1s expression•Lysosome function is required for xbp-1s to increase proteostasis and longevity Expressing the UPRER transcription factor xbp-1s in the neurons or intestine of C. elegans extends lifespan. Imanikia et al. show that neuronal xbp-1s upregulates lysosomal genes and activates lysosomes in the intestine and that intestinal lysosome function is crucial for xbp-1s-mediated increases in proteostasis and longevity.