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The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing

Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells without prior sensitization. One pivotal activating NK receptor is NKG2D, which binds a family of eight ligands, including the major histocompatibility complex (MHC) class I-related chain A (MICA). Human cytomega...

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Autores principales: Seidel, Einat, Dassa, Liat, Schuler, Corinna, Oiknine-Djian, Esther, Wolf, Dana G., Le-Trilling, Vu Thuy Khanh, Mandelboim, Ofer
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118558/
https://www.ncbi.nlm.nih.gov/pubmed/33939764
http://dx.doi.org/10.1371/journal.ppat.1008807
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author Seidel, Einat
Dassa, Liat
Schuler, Corinna
Oiknine-Djian, Esther
Wolf, Dana G.
Le-Trilling, Vu Thuy Khanh
Mandelboim, Ofer
author_facet Seidel, Einat
Dassa, Liat
Schuler, Corinna
Oiknine-Djian, Esther
Wolf, Dana G.
Le-Trilling, Vu Thuy Khanh
Mandelboim, Ofer
author_sort Seidel, Einat
collection PubMed
description Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells without prior sensitization. One pivotal activating NK receptor is NKG2D, which binds a family of eight ligands, including the major histocompatibility complex (MHC) class I-related chain A (MICA). Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus causing morbidity and mortality in immunosuppressed patients and congenitally infected infants. HCMV encodes multiple antagonists of NK cell activation, including many mechanisms targeting MICA. However, only one of these mechanisms, the HCMV protein US9, counters the most prevalent MICA allele, MICA*008. Here, we discover that a hitherto uncharacterized HCMV protein, UL147A, specifically downregulates MICA*008. UL147A primarily induces MICA*008 maturation arrest, and additionally targets it to proteasomal degradation, acting additively with US9 during HCMV infection. Thus, UL147A hinders NKG2D-mediated elimination of HCMV-infected cells by NK cells. Mechanistic analyses disclose that the non-canonical GPI anchoring pathway of immature MICA*008 constitutes the determinant of UL147A specificity for this MICA allele. These findings advance our understanding of the complex and rapidly evolving HCMV immune evasion mechanisms, which may facilitate the development of antiviral drugs and vaccines.
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spelling pubmed-81185582021-05-24 The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing Seidel, Einat Dassa, Liat Schuler, Corinna Oiknine-Djian, Esther Wolf, Dana G. Le-Trilling, Vu Thuy Khanh Mandelboim, Ofer PLoS Pathog Research Article Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells without prior sensitization. One pivotal activating NK receptor is NKG2D, which binds a family of eight ligands, including the major histocompatibility complex (MHC) class I-related chain A (MICA). Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus causing morbidity and mortality in immunosuppressed patients and congenitally infected infants. HCMV encodes multiple antagonists of NK cell activation, including many mechanisms targeting MICA. However, only one of these mechanisms, the HCMV protein US9, counters the most prevalent MICA allele, MICA*008. Here, we discover that a hitherto uncharacterized HCMV protein, UL147A, specifically downregulates MICA*008. UL147A primarily induces MICA*008 maturation arrest, and additionally targets it to proteasomal degradation, acting additively with US9 during HCMV infection. Thus, UL147A hinders NKG2D-mediated elimination of HCMV-infected cells by NK cells. Mechanistic analyses disclose that the non-canonical GPI anchoring pathway of immature MICA*008 constitutes the determinant of UL147A specificity for this MICA allele. These findings advance our understanding of the complex and rapidly evolving HCMV immune evasion mechanisms, which may facilitate the development of antiviral drugs and vaccines. Public Library of Science 2021-05-03 /pmc/articles/PMC8118558/ /pubmed/33939764 http://dx.doi.org/10.1371/journal.ppat.1008807 Text en © 2021 Seidel et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Seidel, Einat
Dassa, Liat
Schuler, Corinna
Oiknine-Djian, Esther
Wolf, Dana G.
Le-Trilling, Vu Thuy Khanh
Mandelboim, Ofer
The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing
title The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing
title_full The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing
title_fullStr The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing
title_full_unstemmed The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing
title_short The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing
title_sort human cytomegalovirus protein ul147a downregulates the most prevalent mica allele: mica*008, to evade nk cell-mediated killing
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118558/
https://www.ncbi.nlm.nih.gov/pubmed/33939764
http://dx.doi.org/10.1371/journal.ppat.1008807
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