Human cytomegalovirus-encoded immune modulators partner to downregulate major histocompatibility complex class I molecules.
Throughout the course of natural evolution with its host, the human cytomegalovirus (HCMV) has developed a variety of strategies to avoid immune recognition and clearance. The major histocompatibility complex (MHC) class I antigen presentation pathway is a major target of the virus. HCMV encodes at least six gene products that modulate the processing of endoplasmic reticulum (ER)-resident MHC class I molecules. Here, we show that two virus-encoded proteins, US2 and US3, coordinate their functions toward the common goal of attenuating class I protein surface expression. In cells stably expressing both US2 and US3, class I molecules were almost completely downregulated from the cell surface. In addition, pulse-chase analysis revealed that the proteasome-dependent turnover of class I molecules occurs more rapidly in cells expressing both US2 and US3 than either US2 or US3 alone. The ability of US3 to retain class I molecules in the ER produces a target-rich environment for US2 to mediate the destruction of class I heavy chains. In fact, expression of US3 enhanced the association between US2 and class I molecules, thus encouraging their dislocation and degradation. This immune evasion strategy ensures that viral antigens are not presented on the cell surface during the early phase of HCMV infection, a critical time of replication and viral proliferation.
Noriega
Vanessa M
VM
Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Tortorella
Domenico
D
D001254:Astrocytoma / Q000821:virology; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000502:physiology*; D015536:Down-Regulation; D005434:Flow Cytometry; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D006868:Hydrolysis; D017874:Immediate-Early Proteins / Q000378:metabolism / Q000502:physiology; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology; D014759:Viral Envelope Proteins / Q000378:metabolism / Q000502:physiology
D006023:Glycoproteins; D015395:Histocompatibility Antigens Class I; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; C118670:US2 protein, Varicellovirus; C095111:US3 protein, cytomegalovirus; D014759:Viral Envelope Proteins