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Multimodal HLA-I genotype regulation by human cytomegalovirus US10 and resulting surface patterning

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 g...

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Hauptverfasser: Gerke, Carolin (VerfasserIn) , Bauersfeld, Liane (VerfasserIn) , Schirmeister, Ivo (VerfasserIn) , Mireisz, Chiara Noemi-Marie (VerfasserIn) , Oberhardt, Valerie (VerfasserIn) , Mery, Lea (VerfasserIn) , Wu, Di (VerfasserIn) , Jürges, Christopher Sebastian (VerfasserIn) , Spaapen, Robbert M. (VerfasserIn) , Mussolino, Claudio (VerfasserIn) , Le, Vu Thuy Khanh (VerfasserIn) , Trilling, Mirko (VerfasserIn) , Dölken, Lars (VerfasserIn) , Paster, Wolfgang (VerfasserIn) , Erhard, Florian (VerfasserIn) , Hofmann, Maike (VerfasserIn) , Schlosser, Andreas (VerfasserIn) , Hengel, Hartmut (VerfasserIn) , Momburg, Frank (VerfasserIn) , Halenius, Anne (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 20 June, 2024
In: eLife
Year: 2024, Jahrgang: 13, Pages: 1-29
ISSN:2050-084X
DOI:10.7554/eLife.85560
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.7554/eLife.85560
Volltext
Verfasserangaben:Carolin Gerke, Liane Bauersfeld, Ivo Schirmeister, Chiara Noemi-Marie Mireisz, Valerie Oberhardt, Lea Mery, Di Wu, Christopher Sebastian Jürges, Robbert M. Spaapen, Claudio Mussolino, Vu Thuy Khanh Le-Trilling, Mirko Trilling, Lars Dölken, Wolfgang Paster, Florian Erhard, Maike Hofmann, Andreas Schlosser, Hartmut Hengel, Frank Momburg, Anne Halenius
Beschreibung
Zusammenfassung: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) β2m-assembled HLA-C, in particular HLA-C*05:01 and -C*12:03, 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.
Beschreibung:Gesehen am 20.02.2025
Beschreibung:Online Resource
ISSN:2050-084X
DOI:10.7554/eLife.85560

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