Cell non-autonomous control of autophagy and metabolism by glial cells

Metcalf, M. G.; Monshietehadi, S.; Sahay, A.; Frakes, A. E.; Durieux, J.; Velichkovska, M.; Mena, C.; Farinas, A.; Sanchez, M.; Dillin, A.

doi:10.1101/2022.12.15.520639

bioRxiv · 10.1101/2022.12.15.520639

Cell non-autonomous control of autophagy and metabolism by glial cells

Metcalf, M. G.·Monshietehadi, S.·Sahay, A.·Frakes, A. E.·Durieux, J.·Velichkovska, M.·Mena, C.·Farinas, A.·Sanchez, M.·Dillin, A.

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Abstract

Glia are the protectors of the nervous system, providing neurons with support and protection from cytotoxic insults. We previously discovered that four astrocyte-like glia can regulate organismal proteostasis and longevity in C. elegans. Expression of the UPRER transcription factor, XBP-1s, in these glia increases stress resistance, longevity, and activates the UPRER in intestinal cells via neuropeptides. Autophagy, a key regulator of metabolism and aging, has been described as a cell autonomous process. Surprisingly, we find that glial XBP-1s enhances proteostasis and longevity by cell non-autonomously reprogramming organismal lipid metabolism and activating autophagy. Glial XBP-1s regulates the activation of another transcription factor, HLH-30/TFEB, in the intestine. HLH-30 activates intestinal autophagy, increases intestinal lipid catabolism, and upregulates a robust transcriptional program. Our study reveals a novel role for glia in regulating peripheral lipid metabolism, autophagy, and organellar health through peripheral activation of HLH-30 and autophagy.

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Metcalf, M. G., Monshietehadi, S., Sahay, A., Frakes, A. E., Durieux, J., Velichkovska, M., Mena, C., Farinas, A., Sanchez, M., Dillin, A.. 2022-12-15. Cell non-autonomous control of autophagy and metabolism by glial cells. https://doi.org/10.1101/2022.12.15.520639

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