Plasma membrane profiling defines an expanded class of cell surface proteins selectively targeted for degradation by HCMV US2 in cooperation with UL141.
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 usi...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-04-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1004811 |
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| author | Jye-Lin Hsu Dick J H van den Boomen Peter Tomasec Michael P Weekes Robin Antrobus Richard J Stanton Eva Ruckova Daniel Sugrue Gavin S Wilkie Andrew J Davison Gavin W G Wilkinson Paul J Lehner |
| author_facet | Jye-Lin Hsu Dick J H van den Boomen Peter Tomasec Michael P Weekes Robin Antrobus Richard J Stanton Eva Ruckova Daniel Sugrue Gavin S Wilkie Andrew J Davison Gavin W G Wilkinson Paul J Lehner |
| author_sort | Jye-Lin Hsu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d057a00df10f4bbdb235d95e59e2cbce |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2015-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-d057a00df10f4bbdb235d95e59e2cbce2025-08-20T02:34:10ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742015-04-01114e100481110.1371/journal.ppat.1004811Plasma membrane profiling defines an expanded class of cell surface proteins selectively targeted for degradation by HCMV US2 in cooperation with UL141.Jye-Lin HsuDick J H van den BoomenPeter TomasecMichael P WeekesRobin AntrobusRichard J StantonEva RuckovaDaniel SugrueGavin S WilkieAndrew J DavisonGavin W G WilkinsonPaul J LehnerHuman 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.https://doi.org/10.1371/journal.ppat.1004811 |
| spellingShingle | Jye-Lin Hsu Dick J H van den Boomen Peter Tomasec Michael P Weekes Robin Antrobus Richard J Stanton Eva Ruckova Daniel Sugrue Gavin S Wilkie Andrew J Davison Gavin W G Wilkinson Paul J Lehner Plasma membrane profiling defines an expanded class of cell surface proteins selectively targeted for degradation by HCMV US2 in cooperation with UL141. PLoS Pathogens |
| title | Plasma membrane profiling defines an expanded class of cell surface proteins selectively targeted for degradation by HCMV US2 in cooperation with UL141. |
| title_full | Plasma membrane profiling defines an expanded class of cell surface proteins selectively targeted for degradation by HCMV US2 in cooperation with UL141. |
| title_fullStr | Plasma membrane profiling defines an expanded class of cell surface proteins selectively targeted for degradation by HCMV US2 in cooperation with UL141. |
| title_full_unstemmed | Plasma membrane profiling defines an expanded class of cell surface proteins selectively targeted for degradation by HCMV US2 in cooperation with UL141. |
| title_short | Plasma membrane profiling defines an expanded class of cell surface proteins selectively targeted for degradation by HCMV US2 in cooperation with UL141. |
| title_sort | plasma membrane profiling defines an expanded class of cell surface proteins selectively targeted for degradation by hcmv us2 in cooperation with ul141 |
| url | https://doi.org/10.1371/journal.ppat.1004811 |
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