human cytomegalovirus ul18 utilizes us6 for evading the nk and t-cell responses人类巨细胞病毒ul18利用us6逃避nk和t细胞反应.pdfVIP

Human Cytomegalovirus UL18 Utilizes US6 for Evading the NK and T-Cell Responses Youngkyun Kim, Boyoun Park, Sunglim Cho, Jinwook Shin, Kwangmin Cho, Youngsoo Jun, Kwangseog Ahn* National Creative Research Initiatives Center for Antigen Presentation, Department of Biological Sciences, Seoul National University, Seoul, Korea Abstract Human cytomegalovirus (HCMV) US6 glycoprotein inhibits TAP function, resulting in down-regulation of MHC class I molecules at the cell surface. Cells lacking MHC class I molecules are susceptible to NK cell lysis. HCMV expresses UL18, a MHC class I homolog that functions as a surrogate to prevent host cell lysis. Despite a high level of sequence and structural homology between UL18 and MHC class I molecules, surface expression of MHC class I, but not UL18, is down regulated by US6. Here, we describe a mechanism of action by which HCMV UL18 avoids attack by the self-derived TAP inhibitor US6. UL18 abrogates US6 inhibition of ATP binding by TAP and, thereby, restores TAP-mediated peptide translocation. In addition, UL18 together with US6 interferes with the physical association between MHC class I molecules and TAP that is required for optimal peptide loading. Thus, regardless of the recovery of TAP function, surface expression of MHC class I molecules remains decreased. UL18 represents a unique immune evasion protein that has evolved to evade both the NK and the T cell immune responses. Citation: Kim Y, Park B, Cho S, Shin J, Cho K, et al. (2008) Human Cytomegalovirus UL18 Utilizes US6 for Evading the NK and T-Cell Responses. PLoS Pathog 4(8): e1000123. doi:10.1371/journal.ppat.1000123 Editor: Jae U. Jung, University of Southern California School of Medicine, United States of America Received February 4, 2008; Accepted July 11, 2008; Published August 8, 2008 Copyright: 2008 Kim et al. This is an open-access article dist