HLA-B locus products resist degradation by the human cytomegalovirus immunoevasin US11

Cosima Zimmermann; Daniel Kowalewski; Liane Bauersfeld; Andreas Hildenbrand; Carolin Gerke; Magdalena Schwarzmüller; Vu Thuy Khanh Le-Trilling; Stefan Stevanovic; Hartmut Hengel; Frank Momburg; Anne Halenius

doi:10.1371/journal.ppat.1008040

HLA-B locus products resist degradation by the human cytomegalovirus immunoevasin US11

PLoS Pathog. 2019 Sep 17;15(9):e1008040. doi: 10.1371/journal.ppat.1008040. eCollection 2019 Sep.

Authors

Cosima Zimmermann^{1

2}, Daniel Kowalewski³, Liane Bauersfeld^{1

2}, Andreas Hildenbrand^{1

2}, Carolin Gerke^{1

2

4

5}, Magdalena Schwarzmüller^{1

2}, Vu Thuy Khanh Le-Trilling⁶, Stefan Stevanovic³, Hartmut Hengel^{1

2}, Frank Momburg⁷, Anne Halenius^{1

2}

Affiliations

¹ Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany.
² Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³ Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
⁴ Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany.
⁵ Faculty of Biology, University of Freiburg, Freiburg, Germany.
⁶ Institute for Virology, University Duisburg-Essen, Essen, Germany.
⁷ Clinical Cooperation Unit Applied Tumor Immunity, Antigen Presentation and T/NK Cell Activation Group, German Cancer Research Center, Heidelberg, Germany.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigen Presentation
Cell Line
Cytomegalovirus / genetics
Cytomegalovirus / immunology*
Cytomegalovirus / metabolism*
Endoplasmic Reticulum-Associated Degradation / immunology
HLA-A Antigens / metabolism
HLA-B Antigens / chemistry
HLA-B Antigens / metabolism*
HeLa Cells
Humans
Immune Evasion
Ligands
Models, Immunological
Models, Molecular
Protein Interaction Domains and Motifs
RNA-Binding Proteins / chemistry
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*
Viral Proteins / chemistry
Viral Proteins / genetics
Viral Proteins / metabolism*

Substances

HLA-A Antigens
HLA-B Antigens
Ligands
RNA-Binding Proteins
US11 protein, herpesvirus
Viral Proteins

Grants and funding

This study was funded by the Deutsche Forschungsgemeinschaft (DFG), HH, He 2526/7-2 and AH, HA 6035/2-1 www.dfg.de; by the Helmholtz Association, HH and AH, Helmholtz VH-VI-424-2, www.helmholtz.de; by the University of Freiburg, AH; HAL1062/15, www.uni-freiburg.de; and by Spemann Graduate School, CG, GSC-4 www.sgbm.uni-freiburg.de. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.