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

Melissa G Metcalf; Samira Monshietehadi; Arushi Sahay; Jenni Durieux; Ashley E Frakes; Martina Velichkovska; Cesar Mena; Amelia Farinas; Melissa Sanchez; Andrew Dillin

doi:10.1016/j.isci.2024.109354

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

iScience. 2024 Feb 28;27(4):109354. doi: 10.1016/j.isci.2024.109354. eCollection 2024 Apr 19.

Authors

Melissa G Metcalf^{1

2}, Samira Monshietehadi^{1

2}, Arushi Sahay^{1

2}, Jenni Durieux^{1

2}, Ashley E Frakes^{1

2}, Martina Velichkovska^{1

2}, Cesar Mena^{1

2}, Amelia Farinas^{1

2}, Melissa Sanchez^{1

2}, Andrew Dillin^{1

2}

Affiliations

¹ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
² Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.

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 UPR^ER transcription factor, XBP-1s, in these glia increases stress resistance, and longevity, and activates the UPR^ER 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.

Keywords: Biological sciences; Cell biology; Functional aspects of cell biology; Neuroscience.