Abstract
The endoplasmic reticulum (ER) is a central eukaryotic organelle with a tubular network made of hairpin proteins linked by hydrolysis of guanosine triphosphate nucleotides. Among posttranslational modifications initiated at the ER level, glycosylation is the most common reaction. However, our understanding of the impact of glycosylation on the ER structure remains unclear. Here, we show that exostosin-1 (EXT1) glycosyltransferase, an enzyme involved in N-glycosylation, is a key regulator of ER morphology and dynamics. We have integrated multiomics and superresolution imaging to characterize the broad effect of EXT1 inactivation, including the ER shape-dynamics-function relationships in mammalian cells. We have observed that inactivating EXT1 induces cell enlargement and enhances metabolic switches such as protein secretion. In particular, suppressing EXT1 in mouse thymocytes causes developmental dysfunctions associated with the ER network extension. Last, our data illuminate the physical and functional aspects of the ER proteome-glycome-lipidome structure axis, with implications in biotechnology and medicine.
Highlights
The endoplasmic reticulum (ER) is one of the largest organelles of eukaryotic cells [1]
In a systematic interactome study, we previously showed that EXT1, an ER-resident type II transmembrane glycosyltransferase, interacts with Notch1, a type I transmembrane receptor that is frequently mutated in cancers [17]
Because the altered phenotype in Notch1-deficient thymocytes was rescued by EXT1 k.o., we concluded that EXT1 may act as a functional suppressor partner of the Notch1 receptor in vivo
Summary
The endoplasmic reticulum (ER) is one of the largest organelles of eukaryotic cells [1] It facilitates communication with other intracellular organelles through its connection to the nuclear envelope and regulates interactions with the external environment via the secretion of proteins, polysaccharides, and lipids [2]. The ER is a complex network of tubules and flat matrices that are in continuous motion. These substructures form a three-dimensional, regularly shaped network, which derives its form from the lipid bilayer and different groups of membrane-associated proteins [4]. The curvature of flat matrices is mediated by the luminal bridging cytoskeleton-linking membrane protein 63 [8]
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