title: A GPI anchor explains the unique biological features of the common NKG2D-ligand allele MICA*008.
abstract: The human MICA (MHC I-related chain A) gene, encoding a ligand for the NKG2D (NKG2-D type II integral membrane protein) receptor, is highly polymorphic. A group of MICA alleles, named MICA 5.1 (prototype, MICA*008), produce a truncated protein due to a nucleotide insertion in the transmembrane domain. These alleles are very frequent in all of the human populations studied and they have different biological properties, compared with full-length alleles, e.g. recruitment into exosomes, which makes them very potent for down-modulating the NKG2D receptor in effector immune cells. Moreover, MICA*008 is not affected by viral immune evasion mechanisms that target other MICA alleles. In the present study, we demonstrate that MICA*008 acquires a GPI (glycosylphosphatidylinositol) anchor and that this modification is responsible for many of the distinct biological features of the truncated MICA alleles, including recruitment of the protein to exosomes. MICA*008 processing is also unusual as it is observed in the endoplasmic reticulum as a Triton™ X-114 soluble protein, partially undergoing GPI modification while the rest is exocytosed, suggesting a new model for MICA*008 release. This is the first report of a GPI-anchored MICA allele. The finding that this modification occurs in both families of human NKG2D ligands, as well as in the murine system, suggests positive pressure to maintain this biochemical feature.
authors.affiliation: Division of Immunology, Department of Pathology, University of Cambridge, UK.
authors.forename: Omodele
authors.initials: O
authors.lastname: Ashiru
authors.forename: Sheila
authors.initials: S
authors.lastname: López-Cobo
authors.forename: Lola
authors.initials: L
authors.lastname: Fernández-Messina
authors.forename: Samuel
authors.initials: S
authors.lastname: Pontes-Quero
authors.forename: Rachele
authors.initials: R
authors.lastname: Pandolfi
authors.forename: Hugh T
authors.initials: HT
authors.lastname: Reyburn
authors.forename: Mar
authors.initials: M
authors.lastname: Valés-Gómez
mesh_terms: D000483:Alleles; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017261:Glycosylphosphatidylinositols / Q000032:analysis; D057809:HEK293 Cells; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D016254:Mutagenesis, Insertional; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012995:Solubility
chemical_list: D058851:GPI-Linked Proteins; D017261:Glycosylphosphatidylinositols; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D008024:Ligands; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011994:Recombinant Proteins