title: Endoplasmic reticulum glycoprotein quality control regulates CD1d assembly and CD1d-mediated antigen presentation.
abstract: The non-classical major histocompatibility complex (MHC) homologue CD1d presents lipid antigens to innate-like lymphocytes called natural-killer T (NKT) cells. These cells, by virtue of their broad cytokine repertoire, shape innate and adaptive immune responses. Here, we have assessed the role of endoplasmic reticulum glycoprotein quality control in CD1d assembly and function, specifically the role of a key component of the quality control machinery, the enzyme UDP glucose glycoprotein glucosyltransferase (UGT1). We observe that in UGT1-deficient cells, CD1d associates prematurely with β2-microglobulin (β2m) and is able to rapidly exit the endoplasmic reticulum. At least some of these CD1d-β2m heterodimers are shorter-lived and can be rescued by provision of a defined exogenous antigen, α-galactosylceramide. Importantly, we show that in UGT1-deficient cells the CD1d-β2m heterodimers have altered antigenicity despite the fact that their cell surface levels are unchanged. We propose that UGT1 serves as a quality control checkpoint during CD1d assembly and further suggest that UGT1-mediated quality control can shape the lipid repertoire of newly synthesized CD1d. The quality control process may play a role in ensuring stability of exported CD1d-β2m complexes, in facilitating presentation of low abundance high affinity antigens, or in preventing deleterious responses to self lipids.
authors.affiliation: Section of Infectious Diseases, Department of Internal Medicine, New Haven, Connecticut 06520-8011.
authors.forename: Amit
authors.initials: A
authors.lastname: Kunte
authors.affiliation: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520-8011.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520-8011.
authors.forename: Crina
authors.initials: C
authors.lastname: Paduraru
authors.affiliation: School of Biosciences, Edgbaston, Birmingham B15 2TT, United Kingdom.
authors.forename: Natacha
authors.initials: N
authors.lastname: Veerapen
authors.affiliation: School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
authors.forename: Liam R
authors.initials: LR
authors.lastname: Cox
authors.affiliation: School of Biosciences, Edgbaston, Birmingham B15 2TT, United Kingdom.
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.affiliation: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520-8011. Electronic address: peter.cresswell@yale.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Cresswell
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000502:physiology*; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005964:Glucosyltransferases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D055503:Protein Multimerization / Q000235:genetics / Q000276:immunology*; D055550:Protein Stability; D021381:Protein Transport / Q000502:physiology; D001613:beta 2-Microglobulin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D055610:Antigens, CD1d; C526879:Cd1d1 protein, mouse; D001613:beta 2-Microglobulin; D005964:Glucosyltransferases
keywords: Antigen Processing; ER Quality Control; Major Histocompatibility Complex (MHC); T cell; Transport