Structural and regulatory diversity shape HLA-C protein expression levels

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DOI

  • Gurman Kaur, MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
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  • Stephanie Gras, Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.
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  • Jesse I Mobbs, Infection and Immunity Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
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  • Julian P Vivian, Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.
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  • Adrian Cortes, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
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  • Thomas Barber, Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
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  • Subita Balaram Kuttikkatte, MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
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  • Lise Torp Jensen
  • Kathrine E Attfield, MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
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  • Calliope A Dendrou, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
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  • Mary Carrington, The Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA.
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  • Gil McVean, Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK.
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  • Anthony W Purcell, Infection and Immunity Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
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  • Jamie Rossjohn, Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
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  • Lars Fugger

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.

Original languageEnglish
JournalNature Communications
Volume8
Pages (from-to)15924
ISSN2041-1723
DOIs
Publication statusPublished - 26 Jun 2017

    Research areas

  • Journal Article

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