Selective involvement of UGGT variant: UGGT2 in protecting mouse embryonic fibroblasts from saturated lipid-induced ER stress.
Hui-Hsing HungYasuko NagatsukaTatiana SoldàVamsi K KodaliKazuhisa IwabuchiHiroyuki KamiguchiKoki KanoIchiro MatsuoKazutaka IkedaAlexandre Rosa CamposMaurizio MolinariPeter GreimelYoshio HirabayashiPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
Keyphrases
- endoplasmic reticulum
- fatty acid
- quality control
- high fat diet induced
- endoplasmic reticulum stress
- insulin resistance
- type diabetes
- magnetic resonance
- single molecule
- cell death
- signaling pathway
- amino acid
- transcription factor
- body mass index
- protein protein
- magnetic resonance imaging
- molecular dynamics simulations
- weight loss
- radiation therapy
- blood pressure
- oxidative stress
- diabetic rats
- physical activity
- adipose tissue
- contrast enhanced
- estrogen receptor
- blood glucose
- structure activity relationship