Inhibition of heavy chain and beta2-microglobulin synthesis as a mechanism of major histocompatibility complex class I downregulation during Epstein-Barr virus replication.
The mechanisms of major histocompatibility complex (MHC) class I downregulation during Epstein-Barr virus (EBV) replication are not well characterized. Here we show that in several cell lines infected with a recombinant EBV strain encoding green fluorescent protein (GFP), the virus lytic cycle coincides with GFP expression, which thus can be used as a marker of virus replication. EBV replication resulted in downregulation of MHC class II and all classical MHC class I alleles independently of viral DNA synthesis or late gene expression. Although assembled MHC class I complexes, the total pool of heavy chains, and beta2-microglobulin (beta2m) were significantly downregulated, free class I heavy chains were stabilized at the surface of cells replicating EBV. Calnexin expression was increased in GFP+ cells, and calnexin and calreticulin accumulated at the cell surface that could contribute to the stabilization of class I heavy chains. Decreased expression levels of another chaperone, ERp57, and TAP2, a transporter associated with antigen processing and presentation, correlated with delayed kinetics of MHC class I maturation. Levels of both class I heavy chain and beta2m mRNA were reduced, and metabolic labeling experiments demonstrated a very low rate of class I heavy chain synthesis in lytically infected cells. MHC class I and MHC class II downregulation was mimicked by pharmacological inhibition of protein synthesis in latently infected cells. Our data suggest that although several mechanisms may contribute to MHC class I downregulation in the course of EBV replication, inhibition of MHC class I synthesis plays the primary role in the process.
Guerreiro-Cacais
Andre Ortlieb
AO
IRIS Center for Strategic Research, Department of Microbiology, Tumor and Cell Biology, Cancer Centrum Karolinska, Karolinska Institute, Stockholm, Sweden.
Uzunel
Mehmet
M
Levitskaya
Jelena
J
Levitsky
Victor
V
D002461:Cell Line, Transformed; D015536:Down-Regulation; D050438:Genes, Immunoglobulin Heavy Chain; D004854:Herpesvirus 4, Human / Q000276:immunology / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D006801:Humans; D014779:Virus Replication / Q000502:physiology*; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D015395:Histocompatibility Antigens Class I; D001613:beta 2-Microglobulin