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Multimodal HLA-I genotype regulation by human cytomegalovirus US10 and resulting surface patterning.
Gerke, Carolin; Bauersfeld, Liane; Schirmeister, Ivo; Mireisz, Chiara Noemi-Marie; Oberhardt, Valerie; Mery, Lea; Wu, Di; Jürges, Christopher Sebastian; Spaapen, Robbert M; Mussolino, Claudio; Le-Trilling, Vu Thuy Khanh; Trilling, Mirko; Dölken, Lars; Paster, Wolfgang; Erhard, Florian; Hofmann, Maike; Schlosser, Andreas; Hengel, Hartmut; Momburg, Frank; Halenius, Anne.
Afiliação
  • Gerke C; Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany.
  • Bauersfeld L; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Schirmeister I; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany.
  • Mireisz CN; Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • Oberhardt V; Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany.
  • Mery L; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Wu D; Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany.
  • Jürges CS; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Spaapen RM; Rudolf Virchow Center, Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany.
  • Mussolino C; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Le-Trilling VTK; Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center University of Freiburg, Freiburg, Germany.
  • Trilling M; Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany.
  • Dölken L; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Paster W; Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany.
  • Erhard F; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Hofmann M; Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
  • Schlosser A; Department of Immunopathology, Sanquin Research, Amsterdam, Netherlands.
  • Hengel H; Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • Momburg F; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Halenius A; Institute for Transfusion Medicine and Gene Therapy, Medical Center University of Freiburg, Freiburg, Germany.
Elife ; 132024 Jun 20.
Article em En | MEDLINE | ID: mdl-38900146
ABSTRACT
Human leucocyte antigen class I (HLA-I) molecules play a central role for both NK and T-cell responses that prevent serious human cytomegalovirus (HCMV) disease. To create opportunities for viral spread, several HCMV-encoded immunoevasins employ diverse strategies to target HLA-I. Among these, the glycoprotein US10 is so far insufficiently studied. While it was reported that US10 interferes with HLA-G expression, its ability to manipulate classical HLA-I antigen presentation remains unknown. In this study, we demonstrate that US10 recognizes and binds to all HLA-I (HLA-A, -B, -C, -E, -G) heavy chains. Additionally, impaired recruitment of HLA-I to the peptide loading complex was observed. Notably, the associated effects varied significantly dependending on HLA-I genotype and allotype (i) HLA-A molecules evaded downregulation by US10, (ii) tapasin-dependent HLA-B molecules showed impaired maturation and cell surface expression, and (iii) ß2m-assembled HLA-C, in particular HLA-C*0501 and -C*1203, and HLA-G were strongly retained in complex with US10 in the endoplasmic reticulum. These genotype-specific effects on HLA-I were confirmed through unbiased HLA-I ligandome analyses. Furthermore, in HCMV-infected fibroblasts inhibition of overlapping US10 and US11 transcription had little effect on HLA-A, but induced HLA-B antigen presentation. Thus, the US10-mediated impact on HLA-I results in multiple geno- and allotypic effects in a so far unparalleled and multimodal manner.
During a viral infection, the immune system must discriminate between healthy and infected cells to selectively kill infected cells. Healthy cells have different types of molecules known collectively as HLA-I on their surface. These molecules present small fragments of proteins from the cell, called antigens, to patrolling immune cells, known as CTLs or natural killer cells. While CTLs ignore antigens from human proteins (which indicate the cell is healthy), they can bind to and recognize antigens from viral proteins, which triggers them to activate immune responses that kill the infected cell. However, some viruses can prevent infected cells from presenting HLA-I molecules on their surfaces as a strategy to evade the immune system. Natural killer cells have evolved to overcome this challenge. They bind to the HLA-I molecules themselves, which causes them to remain inactive. However, if the HLA-I molecules are missing, the NK cells can more easily switch on and kill the target cell. The human cytomegalovirus is a common virus that causes lifelong infection in humans. Although it rarely causes illness in healthy individuals, it can be life-threatening to newborn babies and for individuals with weakened immune systems. One human cytomegalovirus protein known as US10 was previously found to bind to HLA-I without reducing the levels of these molecules on the surface of the cell. However, its precise role remained unclear. Gerke et al. used several biochemical and cell biology approaches to investigate whether US10 manipulates the quality of the three types of HLA-I, which could impact both CTL and NK cell recognition. The experiments showed that US10 acted differently on the various kinds of HLA-I. To one type, it bound strongly within the cell and prevented it from reaching the surface. US10 also prevented another type of HLA-I from maturing properly and presenting antigens but did not affect the third type of HLA-I. These findings suggest that US10 interferes with the ability of different HLA-I types to present antigens in specific ways. Further research is needed to measure how US10 activity affects immune cells, which may ultimately aid the development of new therapies against human cytomegalovirus and other similar viruses.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Antígenos de Histocompatibilidade Classe I / Citomegalovirus Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Antígenos de Histocompatibilidade Classe I / Citomegalovirus Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article