Figure 8

Proposed model for the mechanism by which CRPs, 25-HOC and MBCD interact with autophagy and SVCV entry. It is suggested that these three compounds (their proposed effects are indicated in blue) produce an imbalance in the membrane cholesterol of the lipid rafts, which induces the increase of intracellular ROS. In turn, ROS stimulate the increase in lysosomal pH, which reduces both the fusion of lysosomes and intermediate endosomes (indicated with blue stoppers), and consequently the formation of late endosomes/endolysosomes. Because of their low pH, SVCV requires the formation of endolysosomes to trigger the fusion conformation of the SVCV G protein for viral entry, and a blockade of endolysosomes thus impairs SVCV release into the host’s cytosol. The scheme shows that SVCV endocytic and autophagy pathways share common elements that enable the action of particular autophagy modulators on both of them. The convergence of pathways that may result in the formation of amphisome, as described for other viruses, is also indicated. The positive regulators of both routes are drawn in green, and the negative regulators are presented in red. Artwork drawn and provided by Mr. Diego Sanz.