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Multimodal HLA-I genotype regulation by human cytomegalovirus US10 and resulting surface patterning.
- Source :
-
ELife [Elife] 2024 Jun 20; Vol. 13. Date of Electronic Publication: 2024 Jun 20. - Publication Year :
- 2024
-
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) β <subscript>2</subscript> m-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.<br />Competing Interests: CG, LB, IS, CM, VO, LM, DW, CJ, RS, CM, VL, MT, LD, WP, FE, MH, AS, HH, FM, AH No competing interests declared<br /> (© 2024, Gerke et al.)
- Subjects :
- Humans
Genotype
Viral Proteins genetics
Viral Proteins metabolism
Protein Binding
Host-Pathogen Interactions genetics
Host-Pathogen Interactions immunology
Gene Expression Regulation
Antigen Presentation genetics
Cytomegalovirus genetics
Cytomegalovirus immunology
Histocompatibility Antigens Class I genetics
Histocompatibility Antigens Class I metabolism
Histocompatibility Antigens Class I immunology
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 13
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 38900146
- Full Text :
- https://doi.org/10.7554/eLife.85560