Metcalf ISCIENCE-D-23-07458R1_AGD1724_forward

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”神经胶质细胞（Glia）是神经系统的保护者，可为神经元提供支持并使其免受细胞毒性损伤。我们此前已发现，在秀丽隐杆线虫（C. elegans）中，4类星形胶质样神经胶质细胞可调控机体蛋白质稳态（proteostasis）与寿命。在这类神经胶质细胞中过表达内质网未折叠蛋白反应（UPRER）转录因子XBP-1s，可提升机体应激抵抗能力与寿命，并通过神经肽激活肠细胞内的UPRER通路。自噬（Autophagy）作为代谢与衰老的关键调控因子，此前被认为是一种细胞自主性过程。令人意外的是，我们发现神经胶质细胞中的XBP-1s可通过细胞非自主重编程机体脂质代谢并激活自噬，从而增强机体蛋白质稳态与寿命。神经胶质细胞中的XBP-1s可调控肠道内另一转录因子HLH-30/TFEB的激活过程。HLH-30可激活肠道自噬、促进肠道脂质分解代谢，并上调一套强效的转录调控程序。本研究揭示了神经胶质细胞通过外周激活HLH-30与自噬，进而调控外周脂质代谢、自噬及细胞器健康的全新功能。