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3. Proteomic analysis of circulating immune cells identifies cellular phenotypes associated with COVID-19 severity

Author

Potts, Martin, Fletcher-Etherington, Alice, Nightingale, Katie, Mescia, Federica, Bergamaschi, Laura, Calero-Nieto, Fernando J., Antrobus, Robin, Williamson, James, Parsons, Harriet, Huttlin, Edward L., Kingston, Nathalie, Göttgens, Berthold, Bradley, John R., Lehner, Paul J., Matheson, Nicholas J., Smith, Kenneth G.C., Wills, Mark R., Lyons, Paul A., and Weekes, Michael P.

Published
2023
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6. A prospective study of risk factors associated with seroprevalence of SARS-CoV-2 antibodies in healthcare workers at a large UK teaching hospital

Author

Cooper, Daniel J, Lear, Sara, Watson, Laura, Shaw, Ashley, Ferris, Mark, Doffinger, Rainer, Bousfield, Rachel, Sharrocks, Katherine, Weekes, Michael P., Warne, Ben, Sparkes, Dominic, Jones, Nick K, Rivett, Lucy, Routledge, Matthew, Chaudhry, Afzal, Dempsey, Katherine, Matson, Montgomery, Lakha, Adil, Gathercole, George, O'Connor, Olivia, Wilson, Emily, Shahzad, Orthi, Toms, Kieran, Thompson, Rachel, Halsall, Ian, Halsall, David, Houghton, Sally, Papadia, Sofia, Kingston, Nathalie, Stirrups, Kathleen E, Graves, Barbara, Townsend, Paul, Walker, Neil, Stark, Hannah, De Angelis, Daniela, Seaman, Shaun, Dougan, Gordon, Bradley, John R, Török, M. Estée, Goodfellow, Ian, and Baker, Stephen

Published
2022
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7. SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity

Author

Baker, Stephen, Dougan, Gordon, Hess, Christoph, Kingston, Nathalie, Lehner, Paul J., Lyons, Paul A., Matheson, Nicholas J., Owehand, Willem H., Saunders, Caroline, Summers, Charlotte, Thaventhiran, James E.D., Toshner, Mark, Weekes, Michael P., Maxwell, Patrick, Shaw, Ashley, Bucke, Ashlea, Calder, Jo, Canna, Laura, Domingo, Jason, Elmer, Anne, Fuller, Stewart, Harris, Julie, Hewitt, Sarah, Kennet, Jane, Jose, Sherly, Kourampa, Jenny, Meadows, Anne, O’Brien, Criona, Price, Jane, Publico, Cherry, Rastall, Rebecca, Ribeiro, Carla, Rowlands, Jane, Ruffolo, Valentina, Tordesillas, Hugo, Bullman, Ben, Dunmore, Benjamin J., Fawke, Stuart, Gräf, Stefan, Hodgson, Josh, Huang, Christopher, Hunter, Kelvin, Jones, Emma, Legchenko, Ekaterina, Matara, Cecilia, Martin, Jennifer, Mescia, Federica, O’Donnell, Ciara, Pointon, Linda, Shih, Joy, Sutcliffe, Rachel, Tilly, Tobias, Treacy, Carmen, Tong, Zhen, Wood, Jennifer, Wylot, Marta, Betancourt, Ariana, Bower, Georgie, Cossetti, Chiara, De Sa, Aloka, Epping, Madeline, Gleadall, Nick, Grenfell, Richard, Hinch, Andrew, Jackson, Sarah, Jarvis, Isobel, Krishna, Ben, Nice, Francesca, Omarjee, Ommar, Perera, Marianne, Potts, Martin, Richoz, Nathan, Romashova, Veronika, Stefanucci, Luca, Strezlecki, Mateusz, Turner, Lori, De Bie, Eckart M.D.D., Bunclark, Katherine, Josipovic, Masa, Mackay, Michael, Allison, John, Butcher, Helen, Caputo, Daniela, Clapham-Riley, Debbie, Dewhurst, Eleanor, Furlong, Anita, Graves, Barbara, Gray, Jennifer, Ivers, Tasmin, Le Gresley, Emma, Linger, Rachel, Meloy, Sarah, Muldoon, Francesca, Ovington, Nigel, Papadia, Sofia, Phelan, Isabel, Stark, Hannah, Stirrups, Kathleen E., Townsend, Paul, Walker, Neil, Webster, Jennifer, Scholtes, Ingrid, Hein, Sabine, King, Rebecca, Meng, Bo, Datir, Rawlings, Choi, Jinwook, Bradley, John R., Smith, Kenneth G.C., Lee, Joo Hyeon, and Gupta, Ravindra K.

Published
2022
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8. Epstein-Barr virus BALF0/1 subverts the Caveolin and ERAD pathways to target B cell receptor complexes for degradation.

Author

Pei Tung Yiu, Stephanie, Yifei Liao, Jinjie Yan, Weekes, Michael P., and Gewurz, Benjamin E.

Subjects
B cell receptors, B cells, IMMUNOGLOBULIN heavy chains, B cell lymphoma, CAVEOLAE
Abstract

Epstein-Barr virus (EBV) establishes persistent infection, causes infectious mononucleosis, is a major trigger for multiple sclerosis and contributes to multiple cancers. Yet, knowledge remains incomplete about how the virus remodels host B cells to support lytic replication. We previously identified that EBV lytic replication results in selective depletion of plasma membrane (PM) B cell receptor (BCR) complexes, composed of immunoglobulin and the CD79A and CD79B signaling chains. Here, we used proteomic and biochemical approaches to identify that the EBV early lytic protein BALF0/1 is responsible for EBV lytic cycle BCR degradation. Mechanistically, an immunoglobulin heavy chain (HC) cytoplasmic tail KVK motif was required for ubiquitin-mediated BCR degradation, while CD79A and CD79B were dispensable. BALF0/1 subverted caveolin-mediated endocytosis to internalize PM BCR complexes and to deliver them to the endoplasmic reticulum. BALF0/1 stimulated immunoglobulin HC cytoplasmic tail ubiquitination, which together with the ATPase valosin-containing protein/p97 drove ER-associated degradation of BCR complexes by cytoplasmic proteasomes. BALF0/1 knockout reduced the viral load of secreted EBV particles from B cells that expressed a monoclonal antibody against EBV glycoprotein 350 but not a control anti-influenza hemagglutinin antibody and increased viral particle immunoglobulin incorporation. Consistent with downmodulation of PM BCR, BALF0/1 overexpression reduced viability of a diffuse large B cell lymphoma cell line whose survival is dependent upon BCR signaling. Collectively, our results suggest that EBV BALF0/1 downmodulates immunoglobulin upon lytic reactivation to block BCR signaling and support virion release, but await the development of suitable models to test its roles in EBV reactivation in vivo. [ABSTRACT FROM AUTHOR]

Published
2025
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9. Coagulation factor V is a T-cell inhibitor expressed by leukocytes in COVID-19

Author

Wang, Jun, Kotagiri, Prasanti, Lyons, Paul A., Al-Lamki, Rafia S., Mescia, Federica, Bergamaschi, Laura, Turner, Lorinda, Morgan, Michael D., Calero-Nieto, Fernando J., Bach, Karsten, Mende, Nicole, Wilson, Nicola K., Watts, Emily R., Maxwell, Patrick H., Chinnery, Patrick F., Kingston, Nathalie, Papadia, Sofia, Stirrups, Kathleen E., Walker, Neil, Gupta, Ravindra K., Menon, David K., Allinson, Kieren, Aitken, Sarah J., Toshner, Mark, Weekes, Michael P., Nathan, James A., Walmsley, Sarah R., Ouwehand, Willem H., Kasanicki, Mary, Göttgens, Berthold, Marioni, John C., Smith, Kenneth G.C., Pober, Jordan S., and Bradley, John R.

Published
2022
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11. Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

Author

Aggarwal, Dinesh, Warne, Ben, Jahun, Aminu S., Hamilton, William L., Fieldman, Thomas, du Plessis, Louis, Hill, Verity, Blane, Beth, Watkins, Emmeline, Wright, Elizabeth, Hall, Grant, Ludden, Catherine, Myers, Richard, Hosmillo, Myra, Chaudhry, Yasmin, Pinckert, Malte L., Georgana, Iliana, Izuagbe, Rhys, Leek, Danielle, Nsonwu, Olisaeloka, Hughes, Gareth J., Packer, Simon, Page, Andrew J., Metaxaki, Marina, Fuller, Stewart, Weale, Gillian, Holgate, Jon, Brown, Christopher A., Howes, Rob, McFarlane, Duncan, Dougan, Gordon, Pybus, Oliver G., Angelis, Daniela De, Maxwell, Patrick H., Peacock, Sharon J., Weekes, Michael P., Illingworth, Chris, Harrison, Ewan M., Matheson, Nicholas J., and Goodfellow, Ian G.

Published
2022
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14. Hypoxia inducible factors regulate hepatitis B virus replication by activating the basal core promoter

Author

Wing, Peter A.C., Liu, Peter Jianrui, Harris, James M., Magri, Andrea, Michler, Thomas, Zhuang, Xiaodong, Borrmann, Helene, Minisini, Rosalba, Frampton, Nicholas R., Wettengel, Jochen M., Mailly, Laurent, D’Arienzo, Valentina, Riedl, Tobias, Nobre, Luis, Weekes, Michael P., Pirisi, Mario, Heikenwalder, Mathias, Baumert, Thomas F., Hammond, Ester M., Mole, David R., Protzer, Ulrike, Balfe, Peter, and McKeating, Jane A.

Published
2021
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15. Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease

Author

Bergamaschi, Laura, Mescia, Federica, Turner, Lorinda, Hanson, Aimee L., Kotagiri, Prasanti, Dunmore, Benjamin J., Ruffieux, Hélène, De Sa, Aloka, Huhn, Oisín, Morgan, Michael D., Gerber, Pehuén Pereyra, Wills, Mark R., Baker, Stephen, Calero-Nieto, Fernando J., Doffinger, Rainer, Dougan, Gordon, Elmer, Anne, Goodfellow, Ian G., Gupta, Ravindra K., Hosmillo, Myra, Hunter, Kelvin, Kingston, Nathalie, Lehner, Paul J., Matheson, Nicholas J., Nicholson, Jeremy K., Petrunkina, Anna M., Richardson, Sylvia, Saunders, Caroline, Thaventhiran, James E.D., Toonen, Erik J.M., Weekes, Michael P., Göttgens, Berthold, Toshner, Mark, Hess, Christoph, Bradley, John R., Lyons, Paul A., and Smith, Kenneth G.C.

Published
2021
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16. Rapid implementation of SARS-CoV-2 sequencing to investigate cases of health-care associated COVID-19: a prospective genomic surveillance study

Author

Meredith, Luke W, Hamilton, William L, Warne, Ben, Houldcroft, Charlotte J, Hosmillo, Myra, Jahun, Aminu S, Curran, Martin D, Parmar, Surendra, Caller, Laura G, Caddy, Sarah L, Khokhar, Fahad A, Yakovleva, Anna, Hall, Grant, Feltwell, Theresa, Forrest, Sally, Sridhar, Sushmita, Weekes, Michael P, Baker, Stephen, Brown, Nicholas, Moore, Elinor, Popay, Ashley, Roddick, Iain, Reacher, Mark, Gouliouris, Theodore, Peacock, Sharon J, Dougan, Gordon, Török, M Estée, and Goodfellow, Ian

Published
2020
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18. Point of Care Nucleic Acid Testing for SARS-CoV-2 in Hospitalized Patients: A Clinical Validation Trial and Implementation Study

Author

Baker, Stephen, Bradley, John, Dougan, Gordon, Goodfellow, Ian, Gupta, Ravindra K., Lehner, Paul J., Lyons, Paul, Matheson, Nicholas J., Smith, Kenneth G.C., Toshner, Mark, Weekes, Michael P., Brown, Nick, Curran, Martin, Palmar, Surendra, Zhang, Hongyi, Enoch, David, Chapman, Daniel, Shaw, Ashley, Mendoza, Vivien, Jose, Sherly, Bermperi, Areti, Zerrudo, Julie Ann, Kourampa, Evgenia, Saunders, Caroline, de Jesus, Ranalie, Domingo, Jason, Pasquale, Ciro, Vergese, Bensi, Vargas, Phoebe, Fabiculana, Marivic, Perales, Marlyn, Skells, Richard, Mynott, Lee, Blake, Elizabeth, Bates, Amy, Vallier, Anne-laure, Williams, Alexandra, Phillips, David, Chiu, Edmund, Overhill, Alex, Ramenante, Nicola, Sipple, Jamal, Frost, Steven, Knock, Helena, Hardy, Richard, Foster, Emily, Davidson, Fiona, Rundell, Viona, Bundi, Purity, Abeseabe, Richmond, Clark, Sarah, Vicente, Isabel, Collier, Dami A., Assennato, Sonny M., Warne, Ben, Sithole, Nyarie, Sharrocks, Katherine, Ritchie, Allyson, Ravji, Pooja, Routledge, Matthew, Sparkes, Dominic, Skittrall, Jordan, Smielewska, Anna, Ramsey, Isobel, Goel, Neha, Tassell, Rhys, Lineham, Michelle, Vaghela, Devan, Leong, Clare, Mok, Hoi Ping, Mendoza, Vivienne, Demiris, Nikos, Besser, Martin, Siedner, Mark J., Waddington, Claire S., and Lee, Helen

Published
2020
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22. Suppression of costimulation by human cytomegalovirus promotes evasion of cellular immune defenses

Author

Wang, Eddie C. Y., Pjechova, Mariana, Nightingale, Katie, Vlahava, Virginia-Maria, Patel, Mihil, Ruckova, Eva, Forbes, Simone K., Nobre, Luis, Antrobus, Robin, Roberts, Dawn, Fielding, Ceri A., Seirafian, Sepehr, Davies, James, Murrell, Isa, Lau, Betty, Wilkie, Gavin S., Suárez, Nicolás M., Stanton, Richard J., Vojtesek, Borivoj, Davison, Andrew, Lehner, Paul J., Weekes, Michael P., Wilkinson, Gavin W. G., and Tomasec, Peter

Published
2018

23. High-Definition Analysis of Host Protein Stability during Human Cytomegalovirus Infection Reveals Antiviral Factors and Viral Evasion Mechanisms

Author

Nightingale, Katie, Lin, Kai-Min, Ravenhill, Benjamin J., Davies, Colin, Nobre, Luis, Fielding, Ceri A., Ruckova, Eva, Fletcher-Etherington, Alice, Soday, Lior, Nichols, Hester, Sugrue, Daniel, Wang, Eddie C.Y., Moreno, Pablo, Umrania, Yagnesh, Huttlin, Edward L., Antrobus, Robin, Davison, Andrew J., Wilkinson, Gavin W.G., Stanton, Richard J., Tomasec, Peter, and Weekes, Michael P.

Published
2018
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24. Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax

Author

Gruszczyk, Jakub, Kanjee, Usheer, Chan, Li-Jin, Menant, Sébastien, Malleret, Benoit, Lim, Nicholas T. Y., Schmidt, Christoph Q., Mok, Yee-Foong, Lin, Kai-Min, Pearson, Richard D., Rangel, Gabriel, Smith, Brian J., Call, Melissa J., Weekes, Michael P., Griffin, Michael D. W., Murphy, James M., Abraham, Jonathan, Sriprawat, Kanlaya, Menezes, Maria J., Ferreira, Marcelo U., Russell, Bruce, Renia, Laurent, Duraisingh, Manoj T., and Tham, Wai-Hong

Published
2018

32. HCMV pUL135 Remodels the Actin Cytoskeleton to Impair Immune Recognition of Infected Cells

Author

Stanton, Richard J., Prod’homme, Virginie, Purbhoo, Marco A., Moore, Melanie, Aicheler, Rebecca J., Heinzmann, Marcus, Bailer, Susanne M., Haas, Jürgen, Antrobus, Robin, Weekes, Michael P., Lehner, Paul J., Vojtesek, Borivoj, Miners, Kelly L., Man, Stephen, Wilkie, Gavin S., Davison, Andrew J., Wang, Eddie C.Y., Tomasec, Peter, and Wilkinson, Gavin W.G.

Published
2014
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36. ADAM17 targeting by human cytomegalovirus remodels the cell surface proteome to simultaneously regulate multiple immune pathways.

Author

Rubina, Anzelika, Patel, Mihil, Nightingale, Katie, Potts, Martin, Fielding, Ceri A., Kollnberger, Simon, Lau, Betty, Ladell, Kristin, Miners, Kelly L., Nichols, Jenna, Nobre, Luis, Roberts, Dawn, Trinca, Terrence M., Twohig, Jason P., Vlahava, Virginia-Maria, Davison, Andrew J., Price, David A., Tomasec, Peter, Wilkinson, Gavin W. G., and Weekes, Michael P.

Subjects
HUMAN cytomegalovirus, TUMOR necrosis factor receptors, CELL membranes, RESPONSE inhibition
Abstract

Human cytomegalovirus (HCMV) is a major human pathogen whose life-long persistence is enabled by its remarkable capacity to systematically subvert host immune defenses. In exploring the finding that HCMV infection up-regulates tumor necrosis factor receptor 2 (TNFR2), a ligand for the pro-inflammatory antiviral cytokine TNFα, we found that the underlying mechanism was due to targeting of the protease, A Disintegrin And Metalloproteinase 17 (ADAM17). ADAM17 is the prototype 'sheddase', a family of proteases that cleaves other membrane-bound proteins to release biologically active ectodomains into the supernatant. HCMV impaired ADAM17 surface expression through the action of two virally-encoded proteins in its UL/b' region, UL148 and UL148D. Proteomic plasma membrane profiling of cells infected with an HCMV double-deletion mutant for UL148 and UL148D with restored ADAM17 expression, combined with ADAM17 functional blockade, showed that HCMV stabilized the surface expression of 114 proteins (P < 0.05) in an ADAM17-dependent fashion. These included reported substrates of ADAM17 with established immunological functions such as TNFR2 and jagged1, but also numerous unreported host and viral targets, such as nectin1, UL8, and UL144. Regulation of TNFα-induced cytokine responses and NK inhibition during HCMV infection were dependent on this impairment of ADAM17. We therefore identify a viral immunoregulatory mechanism in which targeting a single sheddase enables broad regulation of multiple critical surface receptors, revealing a paradigm for viral-encoded immunomodulation. [ABSTRACT FROM AUTHOR]

Published
2023
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37. MALARIA: A forward genetic screen identifies erythrocyte CD55 as essential for Plasmodium falciparum invasion

Author

Egan, Elizabeth S., Jiang, Rays H. Y., Moechtar, Mischka A., Barteneva, Natasha S., Weekes, Michael P., Nobre, Luis V., Gygi, Steven P., Paulo, Joao A., Frantzreb, Charles, Tani, Yoshihiko, Takahashi, Junko, Watanabe, Seishi, Goldberg, Jonathan, Paul, Aditya S., Brugnara, Carlo, Root, David E., Wiegand, Roger C., Doench, John G., and Duraisingh, Manoj T.

Published
2015
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38. Selective modulation of cell surface proteins during vaccinia infection: A resource for identifying viral immune evasion strategies.

Author

Depierreux, Delphine M., Altenburg, Arwen F., Soday, Lior, Fletcher-Etherington, Alice, Anthrobus, Robin, Ferguson, Brian J., Weekes, Michael P., and Smith, Geoffrey L.

Subjects
CELL membranes, VACCINIA, CYTOKINE receptors, EPHRINS, KILLER cells, VIRUS diseases
Abstract

The interaction between immune cells and virus-infected targets involves multiple plasma membrane (PM) proteins. A systematic study of PM protein modulation by vaccinia virus (VACV), the paradigm of host regulation, has the potential to reveal not only novel viral immune evasion mechanisms, but also novel factors critical in host immunity. Here, >1000 PM proteins were quantified throughout VACV infection, revealing selective downregulation of known T and NK cell ligands including HLA-C, downregulation of cytokine receptors including IFNAR2, IL-6ST and IL-10RB, and rapid inhibition of expression of certain protocadherins and ephrins, candidate activating immune ligands. Downregulation of most PM proteins occurred via a proteasome-independent mechanism. Upregulated proteins included a decoy receptor for TRAIL. Twenty VACV-encoded PM proteins were identified, of which five were not recognised previously as such. Collectively, this dataset constitutes a valuable resource for future studies on antiviral immunity, host-pathogen interaction, poxvirus biology, vector-based vaccine design and oncolytic therapy. Author summary: Vaccinia virus (VACV) is the vaccine used to eradicate smallpox and an excellent model for studying host-pathogen interactions. Many VACV-mediated immune evasion strategies are known, however how immune cells recognise VACV-infected cells is incompletely understood because of the complexity of surface proteins regulating such interactions. Here, a systematic study of proteins on the cell surface at different times during infection with VACV is presented. This shows not only the precise nature and kinetics of appearance of VACV proteins, but also the selective alteration of cellular surface proteins. The latter thereby identified potential novel immune evasion strategies and host proteins regulating immune activation. Comprehensive comparisons with published datasets provided further insight into mechanisms used to regulate surface protein expression. Such comparisons also identified proteins that are targeted by both VACV and human cytomegalovirus (HCMV), and which are therefore likely to represent host proteins regulating immune recognition and activation. Collectively, this work provides a valuable resource for studying viral immune evasion mechanisms and novel host proteins critical in host immunity. [ABSTRACT FROM AUTHOR]

Published
2022
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41. The Proteasome Distinguishes between Heterotypic and Homotypic Lysine-11-Linked Polyubiquitin Chains

Author

Grice, Guinevere L, Lobb, Ian T, Weekes, Michael P, Gygi, Steven P, Antrobus, Robin, Nathan, James A, Weekes, Michael [0000-0003-3196-5545], Nathan, James [0000-0002-0248-1632], and Apollo - University of Cambridge Repository

Subjects
Proteasome Endopeptidase Complex, Lysine, Molecular Sequence Data, Ubiquitination, complex mixtures, Substrate Specificity, lcsh:Biology (General), Proteolysis, Humans, bacteria, Amino Acid Sequence, Cyclin B1, Polyubiquitin, lcsh:QH301-705.5, HeLa Cells, Protein Binding
Abstract

SummaryProteasome-mediated degradation occurs with proteins principally modified with lysine-48 polyubiquitin chains. Whether the proteasome also can bind atypical ubiquitin chains, including those linked by lysine-11, has not been well established. This is critically important, as lysine-11 polyubiquitination has been implicated in both proteasome-mediated degradation and non-degradative outcomes. Here we demonstrate that pure homotypic lysine-11-linked chains do not bind strongly to the mammalian proteasome. By contrast, heterotypic polyubiquitin chains, containing lysine-11 and lysine-48 linkages, not only bind to the proteasome but also stimulate the proteasomal degradation of the cell-cycle regulator cyclin B1. Thus, while heterotypic lysine-11-linked chains facilitate proteasomal degradation, homotypic lysine-11 linkages adopt conformations that prevent association with the proteasome. Our data demonstrate the capacity of the proteasome to bind ubiquitin chains of distinct topology, with implications for the recognition and diverse biological functions of mixed ubiquitin chains.

Published
2015
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43. Comparative Cell Surface Proteomic Analysis of the Primary Human T Cell and Monocyte Responses to Type I Interferon.

Author

Soday, Lior, Potts, Martin, Hunter, Leah M., Ravenhill, Benjamin J., Houghton, Jack W., Williamson, James C., Antrobus, Robin, Wills, Mark R., Matheson, Nicholas J., and Weekes, Michael P.

Subjects
TYPE I interferons, T cells, SURFACE analysis, VIRAL envelope proteins, INTERFERON beta 1b, GENES, PROTEOMICS
Abstract

The cellular response to interferon (IFN) is essential for antiviral immunity, IFN-based therapy and IFN-related disease. The plasma membrane (PM) provides a critical interface between the cell and its environment, and is the initial portal of entry for viruses. Nonetheless, the effect of IFN on PM proteins is surprisingly poorly understood, and has not been systematically investigated in primary immune cells. Here, we use multiplexed proteomics to quantify IFNα2a-stimulated PM protein changes in primary human CD14+ monocytes and CD4+ T cells from five donors, quantifying 606 and 482 PM proteins respectively. Comparison of cell surface proteomes revealed a remarkable invariance between donors in the overall composition of the cell surface from each cell type, but a marked donor-to-donor variability in the effects of IFNα2a. Furthermore, whereas only 2.7% of quantified proteins were consistently upregulated by IFNα2a at the surface of CD4+ T cells, 6.8% of proteins were consistently upregulated in primary monocytes, suggesting that the magnitude of the IFNα2a response varies according to cell type. Among these differentially regulated proteins, we found the viral target Endothelin-converting enzyme 1 (ECE1) to be an IFNα2a-stimulated protein exclusively upregulated at the surface of CD4+ T cells. We therefore provide a comprehensive map of the cell surface of IFNα2a-stimulated primary human immune cells, including previously uncharacterized interferon stimulated genes (ISGs) and candidate antiviral factors. [ABSTRACT FROM AUTHOR]

Published
2021
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44. Rapid Degradation Pathways of Host Proteins During HCMV Infection Revealed by Quantitative Proteomics.

Author

Lin, Kai-Min, Nightingale, Katie, Soday, Lior, Antrobus, Robin, and Weekes, Michael P.

Subjects
PROTEOMICS, PROTEOLYSIS, VIROLOGY, HUMAN cytomegalovirus, PROTEASOME inhibitors, PROTEINS, PROTEASOMES
Abstract

Human cytomegalovirus (HCMV) is an important pathogen in immunocompromised individuals and neonates, and a paradigm for viral immune evasion. We previously developed a quantitative proteomic approach that identified 133 proteins degraded during the early phase of HCMV infection, including known and novel antiviral factors. The majority were rescued from degradation by MG132, which is known to inhibit lysosomal cathepsins in addition to the proteasome. Global definition of the precise mechanisms of host protein degradation is important both to improve our understanding of viral biology, and to inform novel antiviral therapeutic strategies. We therefore developed and optimized a multiplexed comparative proteomic analysis using the selective proteasome inhibitor bortezomib in addition to MG132, to provide a global mechanistic view of protein degradation. Of proteins rescued from degradation by MG132, 34–47 proteins were also rescued by bortezomib, suggesting both that the predominant mechanism of protein degradation employed by HCMV is via the proteasome, and that alternative pathways for degradation are nevertheless important. Our approach and data will enable improved mechanistic understanding of HCMV and other viruses, and provide a shortlist of candidate restriction factors for further analysis. [ABSTRACT FROM AUTHOR]

Published
2021
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46. Human Cytomegalovirus Long Non-coding RNA1.2 Suppresses Extracellular Release of the Pro-inflammatory Cytokine IL-6 by Blocking NF-κB Activation.

Author

Lau, Betty, Kerr, Karen, Gu, Quan, Nightingale, Katie, Antrobus, Robin, Suárez, Nicolás M., Stanton, Richard J., Wang, Eddie C. Y., Weekes, Michael P., and Davison, Andrew J.

Subjects
HUMAN cytomegalovirus, TUMOR proteins, NUCLEIC acids, TUMOR necrosis factor receptors, GENE expression, VIRAL genes
Abstract

Long non-coding RNAs (lncRNAs) are transcripts of >200 nucleotides that are not translated into functional proteins. Cellular lncRNAs have been shown to act as regulators by interacting with target nucleic acids or proteins and modulating their activities. We investigated the role of RNA1.2, which is one of four major lncRNAs expressed by human cytomegalovirus (HCMV), by comparing the properties of parental virus in vitro with those of deletion mutants lacking either most of the RNA1.2 gene or only the TATA element of the promoter. In comparison with parental virus, these mutants exhibited no growth defects and minimal differences in viral gene expression in human fibroblasts. In contrast, 76 cellular genes were consistently up- or down-regulated by the mutants at both the RNA and protein levels at 72 h after infection. Differential expression of the gene most highly upregulated by the mutants (Tumor protein p63-regulated gene 1-like protein; TPRG1L) was confirmed at both levels by RT-PCR and immunoblotting. Consistent with the known ability of TPRG1L to upregulate IL-6 expression via NF-κB stimulation, RNA1.2 mutant-infected fibroblasts were observed to upregulate IL-6 in addition to TPRG1L. Comparable surface expression of TNF receptors and responsiveness to TNF-α in cells infected by the parental and mutant viruses indicated that activation of signaling by TNF-α is not involved in upregulation of IL-6 by the mutants. In contrast, inhibition of NF-κB activity and knockdown of TPRG1L expression reduced the extracellular release of IL-6 by RNA1.2 mutant-infected cells, thus demonstrating that upregulation of TPRG1L activates NF-κB. The levels of MCP-1 and CXCL1 transcripts were also increased in RNA1.2 mutant-infected cells, further demonstrating the presence of active NF-κB signaling. These results suggest that RNA1.2 plays a role in manipulating intrinsic NF-κB-dependent cytokine and chemokine release during HCMV infection, thereby impacting downstream immune responses. [ABSTRACT FROM AUTHOR]

Published
2020
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47. Human cytomegalovirus degrades DMXL1 to inhibit autophagy, lysosomal acidification, and viral assembly.

Author

Li, Hanqi, Fletcher-Etherington, Alice, Hunter, Leah M., Keshri, Swati, Fielding, Ceri A., Nightingale, Katie, Ravenhill, Benjamin, Nobre, Luis, Potts, Martin, Antrobus, Robin, Crump, Colin M., Rubinsztein, David C., Stanton, Richard J., and Weekes, Michael P.

Abstract

Human cytomegalovirus (HCMV) is an important human pathogen that regulates host immunity and hijacks host compartments, including lysosomes, to assemble virions. We combined a quantitative proteomic analysis of HCMV infection with a database of proteins involved in vacuolar acidification, revealing Dmx-like protein-1 (DMXL1) as the only protein that acidifies vacuoles yet is degraded by HCMV. Systematic comparison of viral deletion mutants reveals the uncharacterized 7 kDa US33A protein as necessary and sufficient for DMXL1 degradation, which occurs via recruitment of the E3 ubiquitin ligase Kip1 ubiquitination-promoting complex (KPC). US33A-mediated DMXL1 degradation inhibits lysosome acidification and autophagic cargo degradation. Formation of the virion assembly compartment, which requires lysosomes, occurs significantly later with US33A-expressing virus infection, with reduced viral replication. These data thus identify a viral strategy for cellular remodeling, with the potential to employ US33A in therapies for viral infection or rheumatic conditions, in which inhibition of lysosome acidification can attenuate disease. [Display omitted] • Systematic proteomic definition of the function of seven HCMV proteins • HCMV US33A hijacks the KPC E3 ligase and is necessary and sufficient to degrade DMXL1 • DMXL1 degradation inhibits lysosomal acidification and autophagic cargo degradation • DMXL1 degradation inhibits virion assembly compartment formation and viral release Li et al. report that human cytomegalovirus (HCMV) US33A degrades DMXL1, a key regulator of vacuolar acidification, to remodel host lysosomes and autophagy. The US33A protein hijacks the cellular KPC E3 ligase complex, inhibiting HCMV assembly and release, as well as suppressing herpes simplex virus replication. [ABSTRACT FROM AUTHOR]

Published
2024
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48. Ubiquitin-Dependent Modification of Skeletal Muscle by the Parasitic Nematode, Trichinella spiralis

Author

White, Rhiannon R., Ponsford, Amy H., Weekes, Michael P., Rodrigues, Rachel B., Ascher, David B., Mol, Marco, Selkirk, Murray E., Gygi, Steven P., Sanderson, Christopher M., and Artavanis-Tsakonas, Katerina

Subjects
PROTEIN, Muscle Proteins, Pathogenesis, Pathology and Laboratory Medicine, Biochemistry, Ligases, Rats, Sprague-Dawley, Database and Informatics Methods, 1108 Medical Microbiology, Tandem Mass Spectrometry, Medicine and Health Sciences, CONJUGATING ENZYME, Post-Translational Modification, PROTEASOME, lcsh:QH301-705.5, Musculoskeletal System, LIGASE, Muscles, Trichinellosis, Helminth Proteins, Enzymes, 1107 Immunology, Host-Pathogen Interactions, Anatomy, Life Sciences & Biomedicine, Sequence Analysis, 0605 Microbiology, Research Article, EXPRESSION, lcsh:Immunologic diseases. Allergy, Motor Proteins, Sequence Databases, Research and Analysis Methods, Microbiology, Host-Parasite Interactions, Molecular Motors, Virology, Parasitic Diseases, Animals, Humans, Immunoprecipitation, QUANTITATIVE PROTEOMICS, Molecular Biology Techniques, Sequencing Techniques, Muscle, Skeletal, Molecular Biology, Trichinella spiralis, Science & Technology, LARVAE, Ubiquitin, Ubiquitination, Biology and Life Sciences, Proteins, IN-VITRO, MASS-SPECTROMETRY, Cell Biology, Rats, Biological Databases, HEK293 Cells, lcsh:Biology (General), Skeletal Muscles, CELLS, Ubiquitin-Conjugating Enzymes, Enzymology, Parasitology, lcsh:RC581-607, Chromatography, Liquid
Abstract

Trichinella spiralis is a muscle-specific parasitic worm that is uniquely intracellular. T. spiralis reprograms terminally differentiated skeletal muscle cells causing them to de-differentiate and re-enter the cell cycle, a process that cannot occur naturally in mammalian skeletal muscle cells, but one that holds great therapeutic potential. Although the host ubiquitin pathway is a common target for viruses and bacteria during infection, its role in parasite pathogenesis has been largely overlooked. Here we demonstrate that the secreted proteins of T. spiralis contain E2 Ub-conjugating and E3 Ub-ligase activity. The E2 activity is attributed to TsUBE2L3, a novel and conserved T. spiralis enzyme located in the secretory organ of the parasite during the muscle stages of infection. TsUBE2L3 cannot function with any T.spiralis secreted E3, but specifically binds to a panel of human RING E3 ligases, including the RBR E3 ARIH2 with which it interacts with a higher affinity than the mammalian ortholog UbcH7/UBE2L3. Expression of TsUBE2L3 in skeletal muscle cells causes a global downregulation in protein ubiquitination, most predominantly affecting motor, sarcomeric and extracellular matrix proteins, thus mediating their stabilization with regards to proteasomal degradation. This effect is not observed in the presence of the mammalian ortholog, suggesting functional divergence in the evolution of the parasite protein. These findings demonstrate the first example of host-parasite interactions via a parasite-derived Ub conjugating enzyme; an E2 that demonstrates a novel muscle protein stabilization function., Author Summary Parasitic worms often establish long-lasting infections in their hosts; tightly regulating their surroundings to strike a delicate balance between host cell modulation and protection that will ensure their replication. This is accomplished via the active secretion of parasite glycolipids and glycoproteins into the host. Trichinella spiralis, a parasitic nematode that infects skeletal muscle of mammals, birds and reptiles, is the only parasitic worm with a true intracellular stage. T. spiralis invade terminally differentiated myotubes, reprogramming them to de-differentiate and re-enter the cell cycle, a process that cannot occur naturally in mammalian skeletal muscle cells, but one that holds great therapeutic potential. We have identified and characterized a novel T. spiralis secreted protein that, despite a high level of sequence identity, appears to have evolved a different function to its host ortholog. This protein is an active Ub conjugating enzyme that binds to a panel of human E3 Ub ligases with higher affinity than the host ortholog. Furthermore, when expressed in skeletal muscle cells in culture, its presence uniquely leads to the stabilization of muscle-specific proteins via the downregulation of their ubiquitination.

Published
2016

49. Epstein-Barr virus subverts mevalonate and fatty acid pathways to promote infected B-cell proliferation and survival.

Author

Wang, Liang Wei, Wang, Zhonghao, Ersing, Ina, Nobre, Luis, Guo, Rui, Jiang, Sizun, Trudeau, Stephen, Zhao, Bo, Weekes, Michael P., and Gewurz, Benjamin E.

Subjects
EPSTEIN-Barr virus, FATTY acids, CHEMICAL inhibitors, LIPOPROTEIN receptors, PROTEIN binding, B cells
Abstract

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with multiple human malignancies. EBV drives B-cell proliferation, which contributes to the pathogenesis of multiple lymphomas. Yet, knowledge of how EBV subverts host biosynthetic pathways to transform resting lymphocytes into activated lymphoblasts remains incomplete. Using a temporal proteomic dataset of EBV primary human B-cell infection, we identified that cholesterol and fatty acid biosynthetic pathways were amongst the most highly EBV induced. Epstein-Barr nuclear antigen 2 (EBNA2), sterol response element binding protein (SREBP) and MYC each had important roles in cholesterol and fatty acid pathway induction. Unexpectedly, HMG-CoA reductase inhibitor chemical epistasis experiments revealed that mevalonate pathway production of geranylgeranyl pyrophosphate (GGPP), rather than cholesterol, was necessary for EBV-driven B-cell outgrowth, perhaps because EBV upregulated the low-density lipoprotein receptor in newly infected cells for cholesterol uptake. Chemical and CRISPR genetic analyses highlighted downstream GGPP roles in EBV-infected cell small G protein Rab activation. Rab13 was highly EBV-induced in an EBNA3-dependent manner and served as a chaperone critical for latent membrane protein (LMP) 1 and 2A trafficking and target gene activation in newly infected and in lymphoblastoid B-cells. Collectively, these studies identify highlight multiple potential therapeutic targets for prevention of EBV-transformed B-cell growth and survival. [ABSTRACT FROM AUTHOR]

Published
2019
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