N-glycosylation of asparagine 8 regulates surface expression of major histocompatibility complex class I chain-related protein A (MICA) alleles dependent on threonine 24
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N-glycosylation of asparagine 8 regulates surface expression of major histocompatibility complex class I chain-related protein A (MICA) alleles dependent on threonine 24. / Pedersen, Maiken Mellergaard; Skovbakke, Sarah Line; Schneider, Christine L.; Lauridsen, Felicia Kathrine Bratt; Andresen, Lars; Jensen, Helle; Skov, Søren.
I: Journal of Biological Chemistry, Bind 289, Nr. 29, 2014, s. 20078-20091.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - N-glycosylation of asparagine 8 regulates surface expression of major histocompatibility complex class I chain-related protein A (MICA) alleles dependent on threonine 24
AU - Pedersen, Maiken Mellergaard
AU - Skovbakke, Sarah Line
AU - Schneider, Christine L.
AU - Lauridsen, Felicia Kathrine Bratt
AU - Andresen, Lars
AU - Jensen, Helle
AU - Skov, Søren
N1 - Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
PY - 2014
Y1 - 2014
N2 - NKG2D is an activating receptor expressed on several types of human lymphocytes. NKG2D ligands can be induced upon cell stress and are frequently targeted post-translationally in infected or transformed cells, in order to avoid immune recognition. Virus infection and inflammation alter protein N-glycosylation and we have previously shown that changes in cellular N-glycosylation, is involved in regulation of NKG2D-ligand surface expression. The specific mode of regulation through N-glycosylation is however unknown. Here we investigated whether direct N-glycosylation of the NKG2D-ligand, MICA itself is critical for cell-surface expression and sought to identify the essential residues. We found that a single N-glycosylation site (N8) was important for MICA018 surface expression. The frequently expressed MICA allele 008, with an altered transmembrane and intracellular domain, was not affected by mutation of this N-glycosylation site. Mutational analysis revealed that a single amino acid (T24) in the extracellular domain of MICA018 was essential for the N-glycosylation dependency, while the intracellular domain was not involved. The HHV7 immunoevasin, U21, was found to inhibit MICA018 surface expression by affecting N-glycosylation and the retention was rescued by T24A substitution. Our study reveals N-glycosylation as an allele-specific regulatory mechanism important for regulation of surface expression of MICA018 and we pinpoint the residues essential for this N-glycosylation dependency. In addition we show that this regulatory mechanism of MICA surface expression is likely targeted during different pathological conditions.
AB - NKG2D is an activating receptor expressed on several types of human lymphocytes. NKG2D ligands can be induced upon cell stress and are frequently targeted post-translationally in infected or transformed cells, in order to avoid immune recognition. Virus infection and inflammation alter protein N-glycosylation and we have previously shown that changes in cellular N-glycosylation, is involved in regulation of NKG2D-ligand surface expression. The specific mode of regulation through N-glycosylation is however unknown. Here we investigated whether direct N-glycosylation of the NKG2D-ligand, MICA itself is critical for cell-surface expression and sought to identify the essential residues. We found that a single N-glycosylation site (N8) was important for MICA018 surface expression. The frequently expressed MICA allele 008, with an altered transmembrane and intracellular domain, was not affected by mutation of this N-glycosylation site. Mutational analysis revealed that a single amino acid (T24) in the extracellular domain of MICA018 was essential for the N-glycosylation dependency, while the intracellular domain was not involved. The HHV7 immunoevasin, U21, was found to inhibit MICA018 surface expression by affecting N-glycosylation and the retention was rescued by T24A substitution. Our study reveals N-glycosylation as an allele-specific regulatory mechanism important for regulation of surface expression of MICA018 and we pinpoint the residues essential for this N-glycosylation dependency. In addition we show that this regulatory mechanism of MICA surface expression is likely targeted during different pathological conditions.
U2 - 10.1074/jbc.M114.573238
DO - 10.1074/jbc.M114.573238
M3 - Journal article
C2 - 24872415
VL - 289
SP - 20078
EP - 20091
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 29
ER -
ID: 113796280