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A bioactive mammalian disaccharide associated with autoimmunity activates a STING-TBK1-dependent immune response

ABSTRACT: DNase III, also known as TREX1, is a 314 amino acid endoplasmic reticulum (ER) tail-anchored 3’ exonuclease where the N-terminal region contains the DNase domain and the C-terminal end controls TREX1 localization to the surface of the ER. Disease mutations in the C-terminal region alters TREX1 ability to interact with the oligosaccharyltransferase (OST) subunits Ribophorin 1 (RPN1) and DDOST leading to rapid hydrolysis of lipid-linked oligosaccharides (LLOs) into bioactive free oligosaccharides (fOS) in a switch-like manner. Bioassay-guided fractionation of the fOS pool revealed that the structure responsible for the bioactivity is a mannose (Man) b1-4 N-acetylglucosamine (GlcNAc) disaccharide. The bioactive disaccharide is produced from OST’s hydrolyzed LLOs in the cytoplasm and activates a STING-TBK1 dependent immune signal that leads to the upregulation of interferon-stimulated genes (ISGs) and chemokine genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE129677 | GEO | 2019/04/16

REPOSITORIES: GEO

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Project description:STT3A and STT3B are the main catalytic subunit of oligosaccharyltransferase (OST-A and OST-B in mammalian cells), which primarily mediate cotranslational and posttranslocational N-linked glycosylation, respectively. To determine the specificity of STT3A and STT3B, we performed proteomics and glycoproteomics analyses to characterize the protein expression and glycosylation in STT3A-knockout (KO), STT3B-KO, and wild-type (WT) HEK293 cells. In total, 3,993 proteins, 4,020 unique N-linked intact glycopeptides (IGPs) and 723 glycosites, representing 401 glycoproteins were identified in KO and WT cells. Deletion of the STT3A gene had a greater impact on the protein expression than deletion of STT3B, especially on glycoproteins. In addition, mannosylated N-glycans from glycoproteins were reduced, while fucosylated N-glycans were increased in STT3A-KO cells. The glycan changes may be caused by the differential expression of glycosyltransferases and the activation of unfolded protein response (UPR) with further analysis of glycan-related enzymes. Interestingly, hyperglycosylated proteins were identified in KO cells. We verified that the hyperglycosylation of ENPL was caused by the ER stress and UPR, which were induced by the deletion of the STT3A. Overall, the specificity of STT3A and STT3B revealed that defects in the OST subunit not only broadly affect N-linked glycosylation of the protein but also affect protein expression.STT3A and STT3B are the main catalytic subunit of oligosaccharyltransferase (OST-A and OST-B in mammalian cells), which primarily mediate cotranslational and posttranslocational N-linked glycosylation, respectively. To determine the specificity of STT3A and STT3B, we performed proteomics and glycoproteomics analyses to characterize the protein expression and glycosylation in STT3A-knockout (KO), STT3B-KO, and wild-type (WT) HEK293 cells. In total, 3,993 proteins, 4,020 unique N-linked intact glycopeptides (IGPs) and 723 glycosites, representing 401 glycoproteins were identified in KO and WT cells. Deletion of the STT3A gene had a greater impact on the protein expression than deletion of STT3B, especially on glycoproteins. In addition, mannosylated N-glycans from glycoproteins were reduced, while fucosylated N-glycans were increased in STT3A-KO cells. The glycan changes may be caused by the differential expression of glycosyltransferases and the activation of unfolded protein response (UPR) with further analysis of glycan-related enzymes. Interestingly, hyperglycosylated proteins were identified in KO cells. We verified that the hyperglycosylation of ENPL was caused by the ER stress and UPR, which were induced by the deletion of the STT3A. Overall, the specificity of STT3A and STT3B revealed that defects in the OST subunit not only broadly affect N-linked glycosylation of the protein but also affect protein expression.

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A bioactive mammalian disaccharide associated with autoimmunity activates a STING-TBK1-dependent immune response

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