The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing
Open Access
- 3 May 2021
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 17 (5), e1008807
- https://doi.org/10.1371/journal.ppat.1008807
Abstract
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. Human cytomegalovirus (HCMV) is a common pathogen that usually causes asymptomatic infection in the immunocompetent population, but the immunosuppressed and fetuses infected in utero suffer mortality and disability due to HCMV disease. Current HCMV treatments are limited and no vaccine has been approved, despite significant efforts. HCMV encodes many genes of unknown function, and virus-host interactions are only partially understood. Here, we discovered that a hitherto uncharacterized HCMV protein, UL147A, downregulates the expression of an activating immune ligand allele named MICA*008, thus hindering the elimination of HCMV-infected cells. Elucidating HCMV immune evasion mechanisms could aid in the development of novel HCMV treatments and vaccines. Furthermore, MICA*008 is a highly prevalent allele implicated in cancer immune evasion, autoimmunity and graft rejection. In this work we have shown that UL147A interferes with MICA*008’s poorly understood, nonstandard maturation pathway, and acts additively with a functionally homologous HCMV protein, US9. Study of UL147A may enable manipulation of its expression as a therapeutic measure against HCMV.Keywords
Funding Information
- Israel Science Foundation (2554/18)
- German-Israeli Foundation for Scientific Research and Development (1412-414.13/2017)
- Israel Cancer Research Fund
- Israeli Science Foundation (442-18)
- Ministry of Science Personal Medicine (3-14764)
- DKFZ-MOST (3-14931)
- Israel Academy of Sciences and Humanities
- Foulkes Foundation
This publication has 78 references indexed in Scilit:
- Human Cytomegalovirus Glycoprotein UL141 Targets the TRAIL Death Receptors to Thwart Host Innate Antiviral DefensesCell Host & Microbe, 2013
- Reevaluation of the Coding Potential and Proteomic Analysis of the BAC-Derived Rhesus Cytomegalovirus Strain 68-1Journal of Virology, 2012
- Human NKG2D-ligands: cell biology strategies to ensure immune recognitionFrontiers in Immunology, 2012
- The Cytomegaloviral Protein pUL138 Acts as Potentiator of Tumor Necrosis Factor (TNF) Receptor 1 Surface Density To Enhance ULb′-Encoded Modulation of TNF-α SignalingJournal of Virology, 2011
- High-resolution human cytomegalovirus transcriptomeProceedings of the National Academy of Sciences of the United States of America, 2011
- Natural Killer Cell Cytotoxicity Is Suppressed by Exposure to the Human NKG2D Ligand MICA*008 That Is Shed by Tumor Cells in ExosomesCancer Research, 2010
- NKG2D Ligand MICA Is Retained in the cis -Golgi Apparatus by Human Cytomegalovirus Protein UL142Journal of Virology, 2009
- High-throughput sequence analysis of variants of human cytomegalovirus strains Towne and AD169Journal of General Virology, 2009
- Adenovirus E3/19K Promotes Evasion of NK Cell Recognition by Intracellular Sequestration of the NKG2D Ligands Major Histocompatibility Complex Class I Chain-Related Proteins A and BJournal of Virology, 2008
- Modulation of natural killer cells by human cytomegalovirusJournal of Clinical Virology, 2008