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A non-canonical arm of UPRER mediates longevity through ER remodeling and lipophagy

Joseph R. Daniele, Ryo Higuchi-Sanabria, Vidhya Ramachandran, Melissa Sanchez, Jenni Durieux, Sarah U. Tronnes, Joseph W. Paul, Daniel J. Esping, Samira Monshietehadi, Melissa G. Metcalf, Andrew Dillin
doi: https://doi.org/10.1101/471177
Joseph R. Daniele
1Department of Molecular & Cellular Biology, Howard Hughes Medical Institute, The Glenn Center for Aging Research, University of California, Berkeley Berkeley, CA 94720-3370
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Ryo Higuchi-Sanabria
1Department of Molecular & Cellular Biology, Howard Hughes Medical Institute, The Glenn Center for Aging Research, University of California, Berkeley Berkeley, CA 94720-3370
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Vidhya Ramachandran
1Department of Molecular & Cellular Biology, Howard Hughes Medical Institute, The Glenn Center for Aging Research, University of California, Berkeley Berkeley, CA 94720-3370
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Melissa Sanchez
1Department of Molecular & Cellular Biology, Howard Hughes Medical Institute, The Glenn Center for Aging Research, University of California, Berkeley Berkeley, CA 94720-3370
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Jenni Durieux
1Department of Molecular & Cellular Biology, Howard Hughes Medical Institute, The Glenn Center for Aging Research, University of California, Berkeley Berkeley, CA 94720-3370
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Sarah U. Tronnes
1Department of Molecular & Cellular Biology, Howard Hughes Medical Institute, The Glenn Center for Aging Research, University of California, Berkeley Berkeley, CA 94720-3370
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Joseph W. Paul
1Department of Molecular & Cellular Biology, Howard Hughes Medical Institute, The Glenn Center for Aging Research, University of California, Berkeley Berkeley, CA 94720-3370
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Daniel J. Esping
2Department of Chemistry, University of Minnesota Minneapolis, MN 55455
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Samira Monshietehadi
1Department of Molecular & Cellular Biology, Howard Hughes Medical Institute, The Glenn Center for Aging Research, University of California, Berkeley Berkeley, CA 94720-3370
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Melissa G. Metcalf
1Department of Molecular & Cellular Biology, Howard Hughes Medical Institute, The Glenn Center for Aging Research, University of California, Berkeley Berkeley, CA 94720-3370
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Andrew Dillin
1Department of Molecular & Cellular Biology, Howard Hughes Medical Institute, The Glenn Center for Aging Research, University of California, Berkeley Berkeley, CA 94720-3370
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  • For correspondence: dillin@berkeley.edu
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ABSTRACT

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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 15, 2018.
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A non-canonical arm of UPRER mediates longevity through ER remodeling and lipophagy
Joseph R. Daniele, Ryo Higuchi-Sanabria, Vidhya Ramachandran, Melissa Sanchez, Jenni Durieux, Sarah U. Tronnes, Joseph W. Paul, Daniel J. Esping, Samira Monshietehadi, Melissa G. Metcalf, Andrew Dillin
bioRxiv 471177; doi: https://doi.org/10.1101/471177
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A non-canonical arm of UPRER mediates longevity through ER remodeling and lipophagy
Joseph R. Daniele, Ryo Higuchi-Sanabria, Vidhya Ramachandran, Melissa Sanchez, Jenni Durieux, Sarah U. Tronnes, Joseph W. Paul, Daniel J. Esping, Samira Monshietehadi, Melissa G. Metcalf, Andrew Dillin
bioRxiv 471177; doi: https://doi.org/10.1101/471177

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