The Cytoplasmic C-Tail of the Mouse Cytomegalovirus 7 Transmembrane Receptor Homologue, M78, Regulates Endocytosis of the Receptor and Modulates Virus Replication in Different Cell Types

摘要: Virus homologues of seven-transmembrane receptors (7TMR) are encoded by all beta- and gammaherpesviruses, suggesting important functional roles. M78 mouse cytomegalovirus (MCMV) is representative a family 7TMR conserved in betaherpesviruses. members have been found to exhibit cell-type specific effects upon virus replication tissue culture affect pathogenesis vivo. We reported previously that M78, for which no ligands known, undergoes rapid, constitutive endocytosis. In this study, we investigated the role cytoplasmic C-tail mediating endocytosis consequences deletion pathogenesis. Mutations (C-tail truncations or point mutations) CCR5-M78 chimeras identified two distinct regions affecting The first was classical acidic di-leucine motif (DDxxxLL), located close C-terminus. second region, activity suppressed downstream sequences, included putative 8th helix, 7th transmembrane domain. A recombinant MCMV expressing an endocytosis-deficient lacking most (M78_CΔ155), had phenotype. M78_CΔ155 restricted bone marrow macrophages, indistinguishable from M78-null recombinant. contrast, replicated normally with enhanced titres wild type other tested cell-types, whereas attenuated. Distinct phenotypes suggest resulted dysfunction, rather than complete loss function; furthermore, they highlight during replication. Infection mice (intranasal) demonstrated M78_CΔ155, similar M78-null, cleared more rapidly lungs severely attenuated salivary glands. It may be speculated attenuation both macrophages contributed their pathogenic phenotypes.