The schematic diagram that illustrates the proposed mechanism of DEN entry.

Left panel (A, B, C) illustrates enlargement of the fusion intermediates corresponding to distinct stages of viral entry shown in the right panel (A',B', C'). A. Initial state of membrane contact. DEN E lays along the surface of the viral envelope. B. Acidification in the presence of AL-free target membrane (for instance, in the early endosome) destabilizes the E dimers and allows E monomers to interact with the target membrane. These interactions result in formation of the earliest hemifusion intermediates that do not support lipid mixing between the membranes. C. Protein E interaction with AL-enriched target membrane (for instance, late endosomal membrane) allows productive insertion of the fusion loop of E required for homotrimerization of E protein. Homotrimers of E drive the transition from restricted hemifusion to complete fusion. The panel on the right (A', B', C') summarizes the proposed pathway of the DEN entry. While endocytosed viral particles in early endosomes are already exposed to environment acidic enough to trigger conformational changes in DEN E (B'), most of the virions neither inactivate nor advance in fusion beyond restricted hemifusion until microtubule-dependent trafficking delivers them into the late endosomal environment and, for the first time during entry, virions come into contact with an AL-enriched target membrane (C'). Virion fusion to the AL BMP-enriched membrane of late endosomes (shown in green) delivers viral RNA to its translation-replication sites at pre- and post-lysosomal vacuoles.

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