Viruses hijack the machinery that controls which proteins sit on the surface of human cells, stripping away the immune system’s early-warning receptors so infections can spread undetected. This matters because the same cellular pathways that viruses exploit to downregulate MHC class I receptors—proteins that flag infected cells for destruction—are also disrupted in cancer and autoimmune disease. Researchers currently lack a complete map of the genes and molecular steps that control receptor display on the cell surface. Without that map, it is difficult to design therapies that restore proper immune recognition in tumours or prevent viral immune evasion. The team has built two new tools to fill this gap. Plasma Membrane Profiling uses mass spectrometry to measure every receptor on a cell’s surface at once, revealing exactly which ones are altered by viruses such as HCMV and HIV. A complementary genetic screen in human haploid cells then pinpoints the specific genes required for those changes. Together, these methods form a discovery platform that can identify both viral tricks and the normal cellular pathways they co-opt. This is fundamental science. It will not produce a drug or diagnostic tomorrow. But understanding how cells regulate their surface receptors—and how viruses short-circuit that regulation—has historically opened routes to immunotherapies and antiviral strategies that were previously invisible.
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The regulated expression of cell surface receptors is an essential feature of cellular homeostasis and is perturbed in diseases such as cancer and intracellular infection. This is exemplified by viruses which alter host receptor expression to enable replication and evade immune recognition. Rather than invent new pathways, viruses appropriate and often accelerate existing cellular pathways, providing unique opportunities to identify regulatory mechanisms of receptor expression, as revealed by o ur work on viral downregulation of MHC class I (MHC-I). Our goal is to find novel genes and map pathways of receptor regulation, and will benefit from new technologies we recently developed: (i) A functional SILAC-based proteomic assay we term Plasma Membrane Profiling allows the unbiased quantification of cell surface receptors, including MHC-I, to provide an unprecedented overview of cellular receptors manipulated by viruses including HCMV and HIV. (ii) To complement this proteomic ap proach we developed a fluorescence-based phenotypic selection for forward genetics in human haploid cells. This allows us to genetically identify the key components of endogenous or virus-appropriated pathways of receptor expression eg ER-associated degradation (ERAD) and plasma membrane quality control. (iii) Combining the above approaches, we use Plasma Membrane Profiling to identify endogenous membrane receptors regulated by the key genes identified in our forward genetics program. Toge ther these technologies provide a unique discovery platform to identify and dissect novel genes and pathways required for viral and endogenous receptor regulation in the secretory pathway.
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