Structural and regulatory diversity shape HLA-C protein expression levels

Gurman Kaur, Stephanie Gras, Jesse I. Mobbs, Julian P. Vivian, Adrian Cortes, Thomas Barber, Subita Balaram Kuttikkatte, Lise Torp Jensen, Kathrine E. Attfield, Calliope A. Dendrou, Mary Carrington, Gil McVean, Anthony W. Purcell, Jamie Rossjohn () and Lars Fugger ()
Additional contact information
Gurman Kaur: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford
Stephanie Gras: Biomedicine Discovery Institute, Monash University
Jesse I. Mobbs: Biomedicine Discovery Institute, Monash University
Julian P. Vivian: Biomedicine Discovery Institute, Monash University
Adrian Cortes: Oxford Centre for Neuroinflammation, John Radcliffe Hospital, University of Oxford
Thomas Barber: Oxford Centre for Neuroinflammation, John Radcliffe Hospital, University of Oxford
Subita Balaram Kuttikkatte: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford
Lise Torp Jensen: Aarhus University Hospital
Kathrine E. Attfield: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford
Calliope A. Dendrou: Oxford Centre for Neuroinflammation, John Radcliffe Hospital, University of Oxford
Mary Carrington: Cancer and Inflammation Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research
Gil McVean: Wellcome Trust Centre for Human Genetics, University of Oxford
Anthony W. Purcell: Biomedicine Discovery Institute, Monash University
Jamie Rossjohn: Biomedicine Discovery Institute, Monash University
Lars Fugger: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Expression of HLA-C varies widely across individuals in an allele-specific manner. This variation in expression can influence efficacy of the immune response, as shown for infectious and autoimmune diseases. MicroRNA binding partially influences differential HLA-C expression, but the additional contributing factors have remained undetermined. Here we use functional and structural analyses to demonstrate that HLA-C expression is modulated not just at the RNA level, but also at the protein level. Specifically, we show that variation in exons 2 and 3, which encode the α1/α2 domains, drives differential expression of HLA-C allomorphs at the cell surface by influencing the structure of the peptide-binding cleft and the diversity of peptides bound by the HLA-C molecules. Together with a phylogenetic analysis, these results highlight the diversity and long-term balancing selection of regulatory factors that modulate HLA-C expression.

Date: 2017
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DOI: 10.1038/ncomms15924

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