Plasma Membrane Profiling Defines an Expanded Class of Cell Surface Proteins Selectively Targeted for Degradation by HCMV US2 in Cooperation with UL141

PLoS Pathogens

Michael P. Weekes¹  Paul J. Lehner¹  Robin Antrobus¹  Jye-Lin Hsu¹  Dick J. H. van den Boomen¹  Gavin S. Wilkie²  Andrew J. Davison²  Eva Ruckova³  Gavin W. G. Wilkinson⁴  Daniel Sugrue⁴  Peter Tomasec⁴  Richard J. Stanton⁴ 

[1] Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom;MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom;Regional Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, Czech Republic;School of Medicine, Cardiff University, Cardiff, United Kingdom

关键词: Integrins;    Membrane proteins;    Cell adhesion;    Cell migration;    NK cells;    Immunoprecipitation;    Cell membranes;    Ligases;   

DOI  :  10.1371/journal.ppat.1004811

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Human cytomegalovirus (HCMV) US2, US3, US6 and US11 act in concert to prevent immune recognition of virally infected cells by CD8+ T-lymphocytes through downregulation of MHC class I molecules (MHC-I). Here we show that US2 function goes far beyond MHC-I degradation. A systematic proteomic study using Plasma Membrane Profiling revealed US2 was unique in downregulating additional cellular targets, including: five distinct integrin α-chains, CD112, the interleukin-12 receptor, PTPRJ and thrombomodulin. US2 recruited the cellular E3 ligase TRC8 to direct the proteasomal degradation of all its targets, reminiscent of its degradation of MHC-I. Whereas integrin α-chains were selectively degraded, their integrin β1 binding partner accumulated in the ER. Consequently integrin signaling, cell adhesion and migration were strongly suppressed. US2 was necessary and sufficient for degradation of the majority of its substrates, but remarkably, the HCMV NK cell evasion function UL141 requisitioned US2 to enhance downregulation of the NK cell ligand CD112. UL141 retained CD112 in the ER from where US2 promoted its TRC8-dependent retrotranslocation and degradation. These findings redefine US2 as a multifunctional degradation hub which, through recruitment of the cellular E3 ligase TRC8, modulates diverse immune pathways involved in antigen presentation, NK cell activation, migration and coagulation; and highlight US2’s impact on HCMV pathogenesis.

【 授权许可】

CC BY