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Isernhagen, A.* ; Schilling, D. ; Monecke, S.* ; Shah, P.* ; Elsner, L.* ; Walter, L.* ; Multhoff, G. ; Dressel, R.*

The MICA-129Met/Val dimorphism affects plasma membrane expression and shedding of the NKG2D ligand MICA.

Immunogenetics 68, 109-123 (2015)
Verlagsversion DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
The MHC class I chain-related molecule A (MICA) is a ligand for the activating natural killer (NK) cell receptor NKG2D. A polymorphism causing a valine to methionine exchange at position 129 affects binding to NKG2D, cytotoxicity, interferon-γ release by NK cells and activation of CD8+ T cells. It is known that tumors can escape NKG2D-mediated immune surveillance by proteolytic shedding of MICA. Therefore, we investigated whether this polymorphism affects plasma membrane expression (pmMICA) and shedding of MICA. Expression of pmMICA was higher in a panel of tumor (n = 16, P = 0.0699) and melanoma cell lines (n = 13, P = 0.0429) carrying the MICA-129Val/Val genotype. MICA-129Val homozygous melanoma cell lines released more soluble MICA (sMICA) by shedding (P = 0.0015). MICA-129Met or MICA-129Val isoforms differing only in this amino acid were expressed in the MICA-negative melanoma cell line Malme, and clones with similar pmMICA expression intensity were selected. The MICA-129Met clones released more sMICA (P = 0.0006), and a higher proportion of the MICA-129Met than the MICA-129Val variant was retained in intracellular compartments (P = 0.0199). The MICA-129Met clones also expressed more MICA messenger RNA (P = 0.0047). The latter phenotype was also observed in mouse L cells transfected with the MICA expression constructs (P = 0.0212). In conclusion, the MICA-129Met/Val dimorphism affects the expression density of MICA on the plasma membrane. More of the MICA-129Met variants were retained intracellularly. If expressed at the cell surface, the MICA-129Met isoform was more susceptible to shedding. Both processes appear to limit the cell surface expression of MICA-129Met variants that have a high binding avidity to NKG2D.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Major Histocompatibility Complex (mhc) Class I Chain-related Molecules A (mica) ; Plasma Membrane Expression ; Proteolytic Shedding ; Single Nucleotide Polymorphism ; Tumor Cells; Chain-related Gene; Nk Cell Activation; Induced Hepatocellular-carcinoma; Genome-wide Association; Class-i; Microsatellite Polymorphism; Repeat Polymorphism; Ulcerative-colitis; Chinese Patients; Han Population
ISSN (print) / ISBN 0093-7711
e-ISSN 1432-1211
Zeitschrift Immunogenetics
Quellenangaben Band: 68, Heft: 2, Seiten: 109-123 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort New York
Begutachtungsstatus Peer reviewed