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

The unfolded protein response of the endoplasmic reticulum (UPR^ER) is a crucial mediator of secretory pathway homeostasis. Expression of the spliced and active form of the UPR^ER transcription factor XBP-1, XBP-1s, in the nervous system triggers activation of the UPR^ER 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 UPR^ER in the intestine through neuronal signaling can increase the activity of lysosomes, leading to extended longevity and improved proteostasis across tissues.