UC Berkeley

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.

Cell non-autonomous signaling of organellar stress response pathways requires the detection of stress, release of a signal, detection of that signal in a separate tissue, and activation of the same stress response pathway in peripheral tissue. Here, I investigate the role of another signaling pathway, TGF-ꞵ, in the cell autonomous and cell non-autonomous signaling pathways of the UPRER, UPRmt, and HSR. Interestingly, I find that knockdown of components in the TGF-ꞵ pathway, specifically the DBL-1/SMA pathway, leads to a myriad of effects on the activation of transcriptional reporters of the UPRER, UPRmt, and HSR.