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

<p>Left panel (<b>A</b>, <b>B</b>, <b>C</b>) illustrates enlargement of the fusion intermediates corresponding to distinct stages of viral entry shown in the right panel (A',B', C'). <b>A.</b> Initial state of membrane contact. DEN E lays along the surface of the viral envelope. <b>B.</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. <b>C.</b> 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 (<b>A'</b>, <b>B'</b>, <b>C'</b>) 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>B'</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 (<b>C'</b>). 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.</p>