Whole-cell and plasma membrane proteomics of herpes simplex virus-1 infection reveals cell surface remodelling via pUL56-mediated GOPC degradation
Herpesviruses are ubiquitous in the human population and they extensively remodel the cellular environment during infection. Multiplexed quantitative proteomic analysis over the time-course of herpes simplex virus (HSV)-1 infection was used to characterize changes in the host-cell proteome and the kinetics of viral protein production. Several host-cell proteins are targeted for rapid degradation by HSV-1, including the cellular trafficking factor GOPC. We show that the poorly-characterized HSV-1 pUL56 directly binds GOPC, stimulating its ubiquitination and proteasomal degradation. Plasma membrane profiling revealed that pUL56 mediates specific changes to the cell surface proteome of infected cells, including loss of IL18 receptor and Toll-like receptor 2, and that cell surface expression of Toll-like receptor 2 is GOPC-dependent. Our study provides significant resources for future investigation of HSV-host interactions and highlights an unanticipated and efficient mechanism whereby a single virus protein targets a cellular trafficking factor to modify the surface of infected cells. This deposition includes quantified peptide data for the five experiments presented in the manuscript. In HSV_UL56_GOPC_Figures3_and_6.xlsx, 090316_Exp relate to the SILAC IP shown in Figure 3, and Exp1_2018_singleshot_SILAC_LMH_Mock_WT_dUL56" and "Exp2_2018_Fraction_SILAC_LMH_Mock_WT_dUL56" relate to the plasma membrane profiling experiment shown in Figure 6.