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

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As the largest human herpesvirus, HCMV is a paradigm of viral immune evasion and has evolved multiple mechanisms to evade immune detection and enable survival. The HCMV genes US2, US3, US6 and US11 promote virus persistence by their ability to downregulate cell surface MHC. We developed ‘Plasma Membrane Profiling’ (PMP), an unbiased SILAC-based proteomics technique to ask whether MHC molecules are the only focus of these genes, or whether additional cellular immunoreceptors are also targeted. PMP compares the relative abundance of cell surface receptors between control and viral gene expressing cells. We found that whereas US3, US6 and US11 were remarkably MHC specific, US2 modulated expression of a wide variety of cell surface immunoreceptors. US2-mediated proteasomal degradation of integrin α-chains blocked integrin signaling and suppressed cell adhesion and migration. All US2 substrates were degraded via the cellular E3 ligase TRC8, and in a remarkable example of cooperativity between HCMV immune-evasins, UL141 requisitioned US2 to target the NK cell ligand CD112 for proteasomal degradation. HCMV US2 and UL141 are therefore modulators of multiple immune-related pathways and act as a multifunctional degradation hub that inhibits the migration, immune recognition and killing of HCMV-infected cells.

Vyšlo v časopise: Plasma Membrane Profiling Defines an Expanded Class of Cell Surface Proteins Selectively Targeted for Degradation by HCMV US2 in Cooperation with UL141. PLoS Pathog 11(4): e32767. doi:10.1371/journal.ppat.1004811
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004811

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