Abstract
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[u], 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[u] 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.
