A bioactive mammalian disaccharide associated with autoimmunity activates STING-TBK1-dependent immune response.
Animals
Autoimmune Diseases
/ genetics
Autoimmunity
/ immunology
Disaccharides
/ immunology
Disease Models, Animal
Endoplasmic Reticulum
Exodeoxyribonucleases
/ genetics
Fibroblasts
Immunity, Innate
/ immunology
Membrane Proteins
/ immunology
Mice
Phosphoproteins
/ genetics
Protein Serine-Threonine Kinases
/ immunology
RAW 264.7 Cells
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
30 05 2019
30 05 2019
Historique:
received:
24
04
2018
accepted:
25
04
2019
entrez:
1
6
2019
pubmed:
31
5
2019
medline:
18
6
2019
Statut:
epublish
Résumé
Glycans from microbial pathogens are well known pathogen-associated molecular patterns that are recognized by the host immunity; however, little is known about whether and how mammalian self-glycans activate the host immune response, especially in the context of autoimmune disease. Using biochemical fractionation and two-dimensional HPLC, we identify an abundant and bioactive free glycan, the Manβ1-4GlcNAc disaccharide in TREX1-associated autoimmune diseases. We report that both monosaccharide residues and the β1-4 linkage are critical for bioactivity of this disaccharide. We also show that Manβ1-4GlcNAc is produced by oligosaccharyltransferase hydrolysis of lipid-linked oligosaccharides in the ER lumen, followed by ENGase and mannosidase processing in the cytosol and lysosomes. Furthermore, synthetic Manβ1-4GlcNAc disaccharide stimulates a broad immune response in vitro, which is in part dependent on the STING-TBK1 pathway, and enhances antibody response in vivo. Together, our data identify Manβ1-4GlcNAc as a novel innate immune modulator associated with chronic autoimmune diseases.
Identifiants
pubmed: 31147550
doi: 10.1038/s41467-019-10319-5
pii: 10.1038/s41467-019-10319-5
pmc: PMC6542856
doi:
Substances chimiques
Disaccharides
0
Membrane Proteins
0
Phosphoproteins
0
Sting1 protein, mouse
0
4-O-mannopyranosyl-2-acetamido-2-deoxyglucose
55637-63-3
Tbk1 protein, mouse
EC 2.7.1.-
Protein Serine-Threonine Kinases
EC 2.7.11.1
Exodeoxyribonucleases
EC 3.1.-
three prime repair exonuclease 1
EC 3.1.16.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2377Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
ID : AR067135
Pays : International
Organisme : NIAMS NIH HHS
ID : R01 AR067135
Pays : United States
Organisme : Welch Foundation
ID : I-1831
Pays : International
Organisme : NIGMS NIH HHS
ID : R56 GM038545
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM038545
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : GM038545
Pays : International
Organisme : NIAID NIH HHS
ID : R56 AI134877
Pays : United States
Organisme : Lupus Research Alliance (Lupus Research Alliance, Inc.)
ID : 585101
Pays : International
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