Structural and regulatory diversity shape HLA-C protein expression levels

Nat Commun. 2017 Jun 26;8:15924. doi: 10.1038/ncomms15924.

Gurman Kaur ¹, Stephanie Gras ² ³, Jesse I Mobbs ², Julian P Vivian ² ³, Adrian Cortes ⁴ ⁵, Thomas Barber ⁴, Subita Balaram Kuttikkatte ¹, Lise Torp Jensen ⁶, Kathrine E Attfield ¹, Calliope A Dendrou ⁴ ⁵, Mary Carrington ⁷ ⁸, Gil McVean ⁵ ⁹, Anthony W Purcell ², Jamie Rossjohn ² ³ ¹⁰, Lars Fugger ¹ ⁴ ⁶

Affiliations

1 MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
2 Infection and Immunity Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
3 Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.
4 Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
5 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
6 Department of Clinical Medicine, Aarhus University Hospital, 8200N Aarhus, Denmark.
7 Cancer and Inflammation Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
8 The Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA.
9 Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK.
10 Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.

PMID: 28649982 DOI: 10.1038/ncomms15924

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.

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