Xbp1 targets canonical UPR^ER and non-canonical pathways in separate tissues to promote longevity

Transcription factors can reprogram gene expression to promote longevity. Here, we investigate the role of Drosophila Xbp1. Xbp1 is activated by splicing of its primary transcript, Xbp1, to generate Xbp1^s, a key activator of the endoplasmic reticulum unfolded protein response (UPR^ER). We show that Xbp1^s induces the conical UPR^ER in the gut, promoting longevity from the resident stem cells. In contrast, in the fat body, Xbp1^s does not appear to trigger UPR^ER but alters metabolic gene expression and is still able to extend lifespan. In the fat body, Xbp1^s and dFOXO impinge on the same target genes, including the PGC-1α orthologue Srl, and dfoxo requires Xbp1 to extend lifespan. Interestingly, unspliceable version of the Xbp1 mRNA, Xbp1 can also extend lifespan, hinting at roles in longevity for the poorly characterized Xbp1^u transcription factor. These findings reveal the diverse functions of Xbp1 in longevity in the fruit fly.