The human cytomegalovirus glycoprotein UL16 selectively mediates intracellular sequestration of the MHC class I-related neonatal Fc receptor (FcRn) for IgG

FcRn transports IgG across polarized epithelial cells, protects IgG from degradation and improves presentation of immune complexed antigens to T cells. FcRn and MHC class I molecules consist of a heavy chain with beta2m. Several pathogens including human cytomegalovirus (HCMV), escape CD8⁺ T or natural killer cell cytotoxicity by destroying MHC class I or its related molecules to prevent antigen presentation. Whether pathogens have similar mechanisms for affecting FcRn is not known. By screening HCMV immune evasion proteins, we found that UL16 binds to FcRn and is a candidate component of immune evasion. Binding was confirmed by immunoprecipitation with lysates from HeLa cells expressing FcRn and UL16. A GST-UL16 protein could bind FcRn from Caco-2 intestinal epithelial cells. UL16-FcRn were co-localized in Caco-2 cells infected with wild-type, but not UL16-deleted HCMV. By using beta2m-null FO-1 cells transfected with FcRn heavy chain alone, we showed that UL16 binding occurred within the ER prior to recruiting beta2m. Confocal microscopy and endoglycosidase digestion revealed that UL16 selectively retained FcRn in the ER and reduced FcRn accumulation in endosomes, and HCMV infection decreased IgG transcytosis across Caco-2 monolayers. Because FcRn is expressed in epithelial, endothelial, macrophage and dendritic cells, the same cells capable of supporting HCMV replication, our results suggest that UL16 sequesters FcRn occurs during virus infection. By inhibiting the capacity of FcRn to bind IgG, the UL16 protein inhibits IgG transcytosis, enhances IgG catabolism in infected cells or tissues, and blocks other FcRn functions that are important for protective immunity against HCMV.