title: Altered microRNA expression after infection with human cytomegalovirus leads to TIMP3 downregulation and increased shedding of metalloprotease substrates, including MICA.
abstract: Proteolytic shedding of ligands for the NK group 2D (NKG2D) receptor is a strategy used by tumors to modulate immune recognition by NK cells and cytotoxic T cells. A number of metalloproteases, especially those of the A disintegrin and metalloprotease (ADAM) family, can mediate NKG2D ligand cleavage and this process can be modulated by expression of the thiol isomerase ERp5. In this article, we describe that an increased shedding of the NKG2D ligand MICA is observed postinfection with several strains of human CMV due to an enhanced activity of ADAM17 (TNF-α converting enzyme) and matrix metalloprotease 14 caused by a reduction in the expression of the endogenous inhibitor of metalloproteases tissue inhibitors of metalloproteinase 3 (TIMP3). This decrease in TIMP3 expression correlates with increased expression of a cellular miRNA known to target TIMP3, and we also identify a human CMV-encoded microRNA able to modulate TIMP3 expression. These observations characterize a novel viral strategy to influence the shedding of cell-surface molecules involved in immune response modulation. They also provide an explanation for previous reports of increased levels of various ADAM17 substrates in the serum from patients with CMV disease. Consistent with this hypothesis, we detected soluble MICA in serum of transplant recipients with CMV disease. Finally, these data suggest that it might be worthwhile to prospectively study ADAM17 activity in a larger group of patients to assay whether this might be a useful biomarker to identify patients at risk for development of CMV disease.
authors: Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain;
authors: Gloria
authors: G
authors: Esteso
authors: Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain;
authors: Elisa
authors: E
authors: Luzón
authors: Transplant Immunology Group, Clinical Immunology Department, University Hospital Gregorio Marañón, 28007 Madrid, Spain;
authors: Elisabeth
authors: E
authors: Sarmiento
authors: Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain;
authors: Ruth
authors: R
authors: Gómez-Caro
authors: Institute for Molecular Medicine, Goethe-University, D-60590 Frankfurt am Main, Germany; and.
authors: Alexander
authors: A
authors: Steinle
authors: Department of Oncology, University of Cambridge, Cancer Research United Kingdom, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, United Kingdom.
authors: Gillian
authors: G
authors: Murphy
authors: Transplant Immunology Group, Clinical Immunology Department, University Hospital Gregorio Marañón, 28007 Madrid, Spain;
authors: Javier
authors: J
authors: Carbone
authors: Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain;
authors: Mar
authors: M
authors: Valés-Gómez
authors: Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain; htreyburn@cnb.csic.es.
authors: Hugh T
authors: HT
authors: Reyburn
mesh_terms: D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D015967:Gene Expression Regulation, Viral / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000378:metabolism*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000097:blood / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D061251:Primary Cell Culture; D013379:Substrate Specificity / Q000235:genetics / Q000276:immunology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000097:blood; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; C098080:MICB antigen; D035683:MicroRNAs; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D053511:Matrix Metalloproteinase 14