Xbp1 targets canonical UPRER and non-canonical pathways in separate tissues to promote longevity
Mengjia Li,
Haocheng Shou,
Guillermo Martínez Corrales,
Tatiana Svermova,
Alessandra Vieira Franco,
Nazif Alic
Affiliations
Mengjia Li
Institute of Healthy Ageing and the Research Department of Genetics, Evolution, and Environment, University College London, London WC1E 6BT, UK
Haocheng Shou
Institute of Healthy Ageing and the Research Department of Genetics, Evolution, and Environment, University College London, London WC1E 6BT, UK
Guillermo Martínez Corrales
Institute of Healthy Ageing and the Research Department of Genetics, Evolution, and Environment, University College London, London WC1E 6BT, UK
Tatiana Svermova
Institute of Healthy Ageing and the Research Department of Genetics, Evolution, and Environment, University College London, London WC1E 6BT, UK
Alessandra Vieira Franco
Institute of Healthy Ageing and the Research Department of Genetics, Evolution, and Environment, University College London, London WC1E 6BT, UK
Nazif Alic
Institute of Healthy Ageing and the Research Department of Genetics, Evolution, and Environment, University College London, London WC1E 6BT, UK; Corresponding author
Summary: 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, Xbp1u, to generate Xbp1s, a key activator of the endoplasmic reticulum unfolded protein response (UPRER). We show that Xbp1s induces the conical UPRER in the gut, promoting longevity from the resident stem cells. In contrast, in the fat body, Xbp1s does not appear to trigger UPRER but alters metabolic gene expression and is still able to extend lifespan. In the fat body, Xbp1s 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, Xbp1u can also extend lifespan, hinting at roles in longevity for the poorly characterized Xbp1u transcription factor. These findings reveal the diverse functions of Xbp1 in longevity in the fruit fly.
