Selective involvement of UGGT variant: UGGT2 in protecting mouse embryonic fibroblasts from saturated lipid-induced ER stress

• DOI: 10.1073/pnas.2214957119
• Publication Date: 2022-12-29T15:36:35Z
• Authors: Hui-Hsing Hung; Yasuko Nagatsuka; Tatiana Soldà; Vamsi K. Kodali; Kazuhisa Iwabuchi; Hiroyuki Kamiguchi; Koki Kano; Ichiro Matsuo; Kazutaka Ikeda; Randal J. Kaufman; Maurizio Molinari; Peter Greimel; Yoshio Hirabayashi
• Keywords: uggt; endoplasmic-reticulum stress; hypoxia; phosphatidic-acid; unfolded protein response; Biological Sciences; Fibroblasts; Endoplasmic Reticulum Stress; Lipids; chop; saturated lipid; Mice; Glucosyltransferases; expression; cells; Animals; glucosyltransferase; activation; phosphatidylglucoside; metabolism; glycoproteins; Glycoproteins

Secretory proteins and lipids are biosynthesized in the endoplasmic reticulum (ER). The “protein quality control” system (PQC) monitors glycoprotein folding and supports the elimination of terminally misfolded polypeptides. A key component of the PQC system is Uridine diphosphate glucose:glycoprotein glucosyltransferase 1 (UGGT1). UGGT1 re-glucosylates unfolded glycoproteins, to enable the re-entry in the protein-folding cycle and impede the aggregation of misfolded glycoproteins. In contrast, a complementary “lipid quality control” (LQC) system that maintains lipid homeostasis remains elusive. Here, we demonstrate that cytotoxic phosphatidic acid derivatives with saturated fatty acyl chains are one of the physiological substrates of UGGT2, an isoform of UGGT1. UGGT2 produces lipid raft-resident phosphatidylglucoside regulating autophagy. Under the disruption of lipid metabolism and hypoxic conditions, UGGT2 inhibits PERK-ATF4-CHOP-mediated apoptosis in mouse embryonic fibroblasts. Moreover, the susceptibility of UGGT2 KO mice to high-fat diet-induced obesity is elevated. We propose that UGGT2 is an ER-localized LQC component that mitigates saturated lipid-associated ER stress via lipid glucosylation.