HLA-B locus products resist degradation by the human cytomegalovirus immunoevasin US11
Open Access
- 17 September 2019
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 15 (9), e1008040
- https://doi.org/10.1371/journal.ppat.1008040
Abstract
To escape CD8+ T-cell immunity, human cytomegalovirus (HCMV) US11 redirects MHC-I for rapid ER-associated proteolytic degradation (ERAD). In humans, classical MHC-I molecules are encoded by the highly polymorphic HLA-A, -B and -C gene loci. While HLA-C resists US11 degradation, the specificity for HLA-A and HLA-B products has not been systematically studied. In this study we analyzed the MHC-I peptide ligands in HCMV-infected cells. A US11-dependent loss of HLA-A ligands was observed, but not of HLA-B. We revealed a general ability of HLA-B to assemble with β2m and exit from the ER in the presence of US11. Surprisingly, a low-complexity region between the signal peptide sequence and the Ig-like domain of US11, was necessary to form a stable interaction with assembled MHC-I and, moreover, this region was also responsible for changing the pool of HLA-B ligands. Our data suggest a two-pronged strategy by US11 to escape CD8+ T-cell immunity, firstly, by degrading HLA-A molecules, and secondly, by manipulating the HLA-B ligandome. The human immune system can cover the presentation of a wide array of pathogen derived antigens owing to the three extraordinary polymorphic MHC class I (MHC-I) gene loci, called HLA-A, -B and -C in humans. Studying the HLA peptide ligands of human cytomegalovirus (HCMV) infected cells, we realized that the HCMV encoded glycoprotein US11 targeted different HLA gene products in distinct manners. More than 20 years ago the first HCMV encoded MHC-I inhibitors were identified, including US11, targeting MHC-I for proteasomal degradation. Here, we describe that the prime target for US11-mediated degradation is HLA-A, whereas HLA-B can resist degradation. Our further mechanistic analysis revealed that US11 uses various domains for distinct functions. Remarkably, the ability of US11 to interact with assembled MHC-I and modify peptide loading of degradation-resistant HLA-B was dependent on a low-complexity region (LCR) located between the signal peptide and the immunoglobulin-like domain of US11. To redirect MHC-I for proteasomal degradation the LCR was dispensable. These findings now raise the intriguing question why US11 has evolved to target HLA-A and -B differentially. Possibly, HLA-B molecules are spared in order to dampen NK cell attack against infected cells.Keywords
Funding Information
- Deutsche Forschungsgemeinschaft (He 2526/7-2)
- Helmholtz-Gemeinschaft (Helmholtz VH-VI-424-2)
- Deutsche Forschungsgemeinschaft (HA 6035/2-1)
This publication has 86 references indexed in Scilit:
- Cytomegalovirus Vectors Violate CD8 + T Cell Epitope Recognition ParadigmsScience, 2013
- Mass Spectrometry Reveals Changes in MHC I Antigen Presentation After Lentivector Expression of a Gene Regulation SystemMolecular Therapy Nucleic Acids, 2013
- HLA-B may be more protective against HIV-1 than HLA-A because it resists negative regulatory factor (Nef) mediated down-regulationProceedings of the National Academy of Sciences of the United States of America, 2012
- Dissecting the role of low-complexity regions in the evolution of vertebrate proteinsBMC Evolutionary Biology, 2012
- The Cytomegaloviral Protein pUL138 Acts as Potentiator of Tumor Necrosis Factor (TNF) Receptor 1 Surface Density To Enhance ULb′-Encoded Modulation of TNF-α SignalingJournal of Virology, 2011
- Human Cytomegalovirus Disrupts the Major Histocompatibility Complex Class I Peptide-Loading Complex and Inhibits Tapasin Gene TranscriptionJournal of Virology, 2011
- Mapping the Landscape of Host-Pathogen Coevolution: HLA Class I Binding and Its Relationship with Evolutionary Conservation in Human and Viral ProteinsJournal of Virology, 2011
- Analysis of interactions in a tapasin/class I complex provides a mechanism for peptide selectionThe EMBO Journal, 2007
- WebLogo: A Sequence Logo Generator: Figure 1Genome Research, 2004
- Reliable prediction of T‐cell epitopes using neural networks with novel sequence representationsProtein Science, 2003