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 B
- 1 May 2008
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 82 (9), 4585-4594
- https://doi.org/10.1128/jvi.02251-07
Abstract
The adenovirus (Ad) early transcription unit 3 (E3) encodes multiple immunosubversive functions that are presumed to facilitate the establishment and persistence of infection. Indeed, the capacity of E3/19K to inhibit transport of HLA class I (HLA-I) to the cell surface, thereby preventing peptide presentation to CD8+T cells, has long been recognized as a paradigm for viral immune evasion. However, HLA-I downregulation has the potential to render Ad-infected cells vulnerable to natural killer (NK) cell recognition. Furthermore, expression of the immediate-early Ad gene E1A is associated with efficient induction of ligands for the key NK cell-activating receptor NKG2D. Here we show that while infection with wild-type Ad enhances synthesis of the NKG2D ligands, major histocompatibility complex class I chain-related proteins A and B (MICA and MICB), their expression on the cell surface is actively suppressed. Both MICA and MICB are retained within the endoplasmic reticulum as immature endoglycosidase H-sensitive forms. By analyzing a range of cell lines and viruses carrying mutated versions of the E3 gene region, E3/19K was identified as the gene responsible for this activity. The structural requirements within E3/19K necessary to sequester MICA/B and HLA-I are similar. In functional assays, deletion of E3/19K rendered Ad-infected cells more sensitive to NK cell recognition. We report the first NK evasion function in theAdenoviridaeand describe a novel function for E3/19K. Thus, E3/19K has a dual function: inhibition of T-cell recognition and NK cell activation.This publication has 58 references indexed in Scilit:
- Adenovirus vector delivery stimulates natural killer cell recognitionJournal of General Virology, 2007
- MICA Allele-Level Typing by Sequence-based Typing with Computerized Assignment of Polymorphic Sites and Short Tandem Repeats within the Transmembrane RegionHuman Immunology, 2006
- The Endoplasmic Reticulum Lumenal Domain of the Adenovirus Type 2 E3-19K Protein Binds to Peptide-Filled and Peptide-Deficient HLA-A*1101 MoleculesJournal of Virology, 2005
- The DNA damage pathway regulates innate immune system ligands of the NKG2D receptorNature, 2005
- Downregulation of natural killer cell–activating ligand CD155 by human cytomegalovirus UL141Nature Immunology, 2005
- Activation of NK Cells and T Cells by NKG2D, a Receptor for Stress-Inducible MICAScience, 1999
- Crystal Structure of the MHC Class I Homolog MIC-A, a γδ T Cell LigandImmunity, 1999
- Identification of class I MHC regions which bind to the adenovirus E3-19k proteinMolecular Immunology, 1994
- HLA-A- and HLA-B-specific monoclonal antibodies reactive with free heavy chains in Western blots, in formalin-fixed, paraffin-embedded tissue sections and in cryo-immuno-electron microscopyInternational Immunology, 1990
- An adenovirus type 2 glycoprotein blocks cell surface expression of human histocompatibility class I antigensCell, 1985