title: Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands.
abstract: Tumour-associated ligands of the activating NKG2D (natural killer group 2, member D; also called KLRK1) receptor-which are induced by genotoxic or cellular stress-trigger activation of natural killer cells and co-stimulation of effector T cells, and may thus promote resistance to cancer. However, many progressing tumours in humans counter this anti-tumour activity by shedding the soluble major histocompatibility complex class-I-related ligand MICA, which induces internalization and degradation of NKG2D and stimulates population expansions of normally rare NKG2D+CD4+ T cells with negative regulatory functions. Here we show that on the surface of tumour cells, MICA associates with endoplasmic reticulum protein 5 (ERp5; also called PDIA6 or P5), which, similar to protein disulphide isomerase, usually assists in the folding of nascent proteins inside cells. Pharmacological inhibition of thioreductase activity and ERp5 gene silencing revealed that cell-surface ERp5 function is required for MICA shedding. ERp5 and membrane-anchored MICA form transitory mixed disulphide complexes from which soluble MICA is released after proteolytic cleavage near the cell membrane. Reduction of the seemingly inaccessible disulphide bond in the membrane-proximal alpha3 domain of MICA must involve a large conformational change that enables proteolytic cleavage. These results uncover a molecular mechanism whereby domain-specific deconstruction regulates MICA protein shedding, thereby promoting tumour immune evasion, and identify surface ERp5 as a strategic target for therapeutic intervention.
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA.
authors.forename: Brett K
authors.initials: BK
authors.lastname: Kaiser
authors.forename: Daesong
authors.initials: D
authors.lastname: Yim
authors.forename: I-Ting
authors.initials: IT
authors.lastname: Chow
authors.forename: Segundo
authors.initials: S
authors.lastname: Gonzalez
authors.forename: Zhenpeng
authors.initials: Z
authors.lastname: Dai
authors.forename: Henning H
authors.initials: HH
authors.lastname: Mann
authors.forename: Roland K
authors.initials: RK
authors.lastname: Strong
authors.forename: Veronika
authors.initials: V
authors.lastname: Groh
authors.forename: Thomas
authors.initials: T
authors.lastname: Spies
mesh_terms: D045744:Cell Line, Tumor; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D018832:Molecular Chaperones / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism*; D011485:Protein Binding; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D013379:Substrate Specificity
chemical_list: D004220:Disulfides; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D008024:Ligands; C099187:MHC class I-related chain A; D018832:Molecular Chaperones; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D019704:Protein Disulfide-Isomerases