RT Journal Article SR Electronic T1 A non-canonical arm of UPRER mediates longevity through ER remodeling and lipophagy JF bioRxiv FD Cold Spring Harbor Laboratory SP 471177 DO 10.1101/471177 A1 Daniele, Joseph R. A1 Higuchi-Sanabria, Ryo A1 Ramachandran, Vidhya A1 Sanchez, Melissa A1 Durieux, Jenni A1 Tronnes, Sarah U. A1 Paul, Joseph W. A1 Esping, Daniel J. A1 Monshietehadi, Samira A1 Metcalf, Melissa G. A1 Dillin, Andrew YR 2018 UL http://biorxiv.org/content/early/2018/11/15/471177.abstract AB Longevity is dictated by a combination of environmental and genetic factors. One of the key mechanisms implicated in regulating lifespan extension is the ability to induce protein chaperones to promote protein homeostasis. However, it is unclear whether protein chaperones exclusively regulate longevity. Previous work has shown that activating the unfolded protein response of the endoplasmic reticulum (UPRER) in neurons can signal peripheral tissues to promote chaperone expression, thus enhancing organismal stress resistance and extending lifespan. Here, we find that this activation not only promotes chaperones, but facilitates a dramatic restructuring of ER morphology in intestinal cells. This restructuring, which includes depletion of lipid droplets, ER expansion, and ER tubulation, depends of lipophagy. Surprisingly, we find that lipophagy is required for lifespan extension and is completely independent of chaperone function. Therefore, UPR induction in neurons triggers two distinct programs in the periphery: the canonical arm through protein chaperones, and a non-canonical mechanism through lipid depletion. In summary, our study identifies lipophagy as an integral component of UPRER-induced longevity.