title: Human cytomegalovirus-encoded US2 and US11 target unassembled MHC class I heavy chains for degradation.
abstract: Surface MHC class I molecules serve important immune functions as ligands for both T and NK cell receptors for the elimination of infected and malignant cells. In order to reach the cell surface, MHC class I molecules have to fold properly and form trimers consisting of a heavy chain (HC), a beta2-microglobulin light chain and an 8-10-mer peptide. A panel of ER chaperones facilitates the folding and assembly process. Incorrectly assembled or folded MHC class I HCs are detected by the ER quality-control system and transported to the cytosol for degradation by proteasomes. In human cytomegalovirus-infected cells, two viral proteins are synthesized, US2 and US11, which target MHC class I HCs for proteasomal degradation. It is unknown at which stage of MHC class I folding and complex formation US2 and US11 come into play. In addition, it is unclear if the disposal takes place via the same pathway through which proteins are removed that fail to pass ER quality control. In this study, we show with a beta2m-deficient cell line that US2 and US11 both target unassembled HCs for degradation. This suggests that US2 and US11 both act at an early stage of MHC class I complex formation. In addition, our data indicate that US11-mediated degradation involves mechanisms that are similar to those normally used to remove terminally misfolded HCs.
authors.affiliation: Department of Medical Microbiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Martine T
authors.initials: MT
authors.lastname: Barel
authors.forename: Gerco C
authors.initials: GC
authors.lastname: Hassink
authors.forename: Sjaak
authors.initials: S
authors.lastname: van Voorden
authors.forename: Emmanuel J H J
authors.initials: EJ
authors.lastname: Wiertz
mesh_terms: D003587:Cytomegalovirus / Q000235:genetics*; D003600:Cytosol / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010084:Oxidation-Reduction; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014759:Viral Envelope Proteins; D014764:Viral Proteins / Q000378:metabolism*; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D061988:Proteasome Inhibitors; D016601:RNA-Binding Proteins; C074546:US11 protein, herpesvirus; C118670:US2 protein, Varicellovirus; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D001613:beta 2-Microglobulin