Journal Article

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

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

2019

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Antigen Presentation / Backup software / Biology / Biology and life sciences / C gene / CD8 antigen / Cell Line / Cytomegalovirus / Cytomegalovirus - genetics / Cytomegalovirus - immunology / Cytomegalovirus - metabolism / Cytomegaloviruses / Degradation / Endoplasmic Reticulum-Associated Degradation - immunology / Fibroblasts / Gene expression / Health aspects / HeLa Cells / Histocompatibility antigen HLA / Histocompatibility antigens / HLA antigens / HLA histocompatibility antigens / HLA-A Antigens - metabolism / HLA-B Antigens - chemistry / HLA-B Antigens - metabolism / Humans / Immune Evasion / Immunity / Immunoglobulins / Immunology / Ligands / Loci / Lymphocytes T / Major histocompatibility complex / Medicine / Medicine and Health Sciences / Models, Immunological / Models, Molecular / Peptides / Protein binding / Protein Interaction Domains and Motifs / Proteolysis / Research and analysis methods / RNA-Binding Proteins - chemistry / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / T cells / Tumor necrosis factor-TNF / Viral Proteins - chemistry / Viral Proteins - genetics / Viral Proteins - metabolism / Virology