Integrin β3 α2,6-sialylation by the sialyltransferase ST6Gal1 promotes human cytomegalovirus entry into fibroblasts.

The interactions between viral ligands and cellular receptors, along with the subsequent entry of Human cytomegalovirus (HCMV) into host cells, represent an important focus of research in virus-host relationships. This study investigated the function and mechanistic role of α2,6-sialylation of Integrin β3 during the early stages of infection in fibroblasts. Analysis of the human Integrin β3 glycomics database revealed that the surface glycans of Integrin β3 are extensively modified with terminal sialic acid residues and occur at relatively high abundance. To evaluate their functional relevance, Integrin β3-knockout cells and α2,6-sialyltransferase ST6Gal1-knockdown cells were established. Quantitative PCR, flow cytometry, and immunofluorescence analyses confirmed that α2,6-sialylation of Integrin β3 is required for viral internalization, and the absence of this modification significantly reduced viral entry into host cells. This observation was further validated through additional virological assays designed to detect viral infection. Mechanistic analysis demonstrated that defective α2,6-sialylation of Integrin β3 impairs the interaction between viral receptors and ligands, preventing activation of the viral entry signaling pathways, Integrin-Src, and resulting in impaired HCMV-induced Rho A-cofilin inactivation. These findings broaden the current understanding of early HCMV infection and highlight ST6Gal1 and Integrin β3 α2,6-sialylation as potential glycobiological targets for therapeutic intervention.