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Professor Paul Lehner

Departments

Department of Medicine:
Wellcome Trust Senior Clinical Fellow and Honorary Consultant
Cambridge Institute for Medical Research:

Research Interests

Viral immune evasion mechanisms

We are interested in viral evasion of the immune system. As the ultimate intracellular parasites, viruses target the host cellular machinery to enable their replication and avoid elimination by the immune system. Our research goals and themes are to use functional genetic and proteomic technologies to identify novel cellular receptors manipulated by viruses, understand why these receptors are targeted and elucidate the mechanisms used by viruses to manipulate the cellular immunoreceptors.

Why is the study of viral evasion mechanisms of interest?

Identifying host cellular receptors targeted by viruses is important for several reasons: Viruses are assiduous cell biologists. Studying the critical host receptors targeted by viruses and understanding the mechanisms they use to manipulate cellular processes provides unique insights into fundamental cell biological pathways, teaches us about viral pathogenesis and has the capacity to offer novel therapeutic approaches, for instance by targeting these newly identified receptors.

Viral regulation of cell surface receptors

Cell surface receptors are modulated by all intracellular pathogens. Our work on viral evasion of the MHC class I antigen presentation pathway has driven our interest in the role of ubiquitin in immunoreceptor regulation. We identified the K3 and K5 viral ubiquitin E3 ligases which ubiquitinate, downregulate and degrade cell surface MHC I molecules via the endolysosomal pathway. A major goal has been to develop unbiased methods to identify cell surface receptors up- or downregulated by viruses. Using SILAC-based proteomics we can differentially analyse >600 plasma membrane proteins, and therefore identify those receptors whose expression is altered by viruses. This technology has identified immune evasion as well as metabolic receptors whose expression is dramatically altered following infection.

Defining the mechanism of action of these novel receptors

Using genetic, biochemical and cell biological approaches we then determine how newly identified cell surface proteins are compromised by intracellular pathogens. For example, our siRNA screens identified novel E3 ligases, such as TRC8, involved in receptor regulation as well as their physiological substrates. We use traditional biochemical as well as novel insertional mutagenesis-based genetic screens to identify the critical pathway components required for immunoreceptor regulation.

Group members:

Helen Bye

Florencia Cano

Lidia Duncan

Nicholas Matheson

Radu Rapiteanu

Shireen Tan

Iva Tchasovnikarova

Richard Timms

Dick van den Boomen

Michael Weekes

Keywords

co-stimulation ; confocal microscopy ; proteomics ; co-stimulatory molecules ; CTL ; mass spectrometry ; ubiquitin E3 ligase ; antigen presentation ; ubiquitin ; vaccines ; cytotoxic T cells (CTL) ; heat shock proteins (hsp) ; SILAC ; antigen processing ; MHC class I ; MHC ; human studies ; animal models ; fluorescence microscopy ; FACS ; dendritic cells

Topics

  • herpesviruses

Key Publications

Weekes MP, Tomasec P, Huttlin EL, Fielding CA, Nusinow CA,  Stanton RJ, Wang ECY, Aicheler R,Murrell I, Wilkinson GWG, Lehner PJ,  Gygi SP 2014 Quantitative Temporal Viromics: An Approach to Investigate Host-Pathogen Interaction Cell 157, Issue 6, p1460–1472

Weekes MP, Tan SY, Poole E, Talbot S, Antrobus R, Smith DL, Montag C, Gygi SP, Sinclair JH, Lehner PJ. (2013) Latency-associated degradation of the MRP1 drug transporter during latent human cytomegalovirus infection. Science 340, 199-202.

Cano F, Bye H, Duncan LM, Buchet-Poyau K, Billaud M, Wills MR, Lehner PJ. The RNA-binding E3 ubiquitin ligase MEX-3C links ubiquitination with MHC-I mRNA degradation. EMBO J. (2012) Aug 29;31(17):3596-606.

Duncan LM, Timms RT, Zavodszky E, Cano F, Dougan G, Randow, F and Lehner, PJ. Fluorescence-Based Phenotypic Selection Allows Forward Genetic Screens in Haploid Human Cells. PLoS ONE (2012) 7(6): e39651.

Burr ML, Cano F, Svobodova S, Boyle LH, Boname JM, Lehner PJ. HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation. Proc Natl Acad Sci (2011) 108:2034-9

Stagg, HR, Thomas M, Van den Boomen D, Wiertz EH, Drabkin HA, Gemmill RM and Lehner PJ. The TRC8 E3 Ligase ubiquitinates MHC class I molecules before dislocation from the ER Journal of Cell Biology (2009) 186(5):685-92

Randow F, Lehner PJ.  Viral avoidance and exploitation of the ubiquitin system. Nature Cell Biology (2009)11(5):527-34.

Thomas, M, Boname, JM, Field, S, Nejentsev, S, Salio, M, Cerundolo, V, Wills M, Lehner PJ. Downregulation of NKG2D and NKp80 ligands by Kaposi’s sarcoma-associated herpesvirus K5 protects against NK cell cytotoxicity Proc Natl Acad Sci (2008)105:1656-61