Protein-driven membrane remodeling: Molecular perspectives from Flaviviridae infections

The mammalian cell membrane consists of thousands of different lipid species, and this variety is critical for bio-logical function. Alterations to this balance can be dangerous as they can lead to permanent disruption of lipid metabolism, a hallmark in several viral diseases. The Flaviviridae family is made up of positive single-stranded RNA viruses that assemble at or near the location of lipid droplet formation in the endoplasmic reticulum. These viruses are known to interfere with lipid metabolism during the onset of liver disease, albeit to different extents. Pathogenesis of these infections involves specific pro-tein-lipid interactions that alter lipid sorting and metabolism to sustain propagation of the viral infection. Recent experimental studies identify a correlation between viral proteins and lipid content or location in the cell, but these do not assess mem-brane-embedded interactions. Molecular modeling, specifically molecular dynamics simulations, can provide molecular-level spatial and temporal resolution for characterization of biomolecular interactions. This review focuses on recent advancements and current knowledge gaps in the molecular mechanisms of lipid-mediated liver disease preceded by viral infection. We discuss three viruses from the Flaviviridae family: dengue, zika, and hepatitis C, with a particular focus on lipid interactions with their respective ion channels, known as viroporins.

Automated summary

The mammalian cell membrane is composed of a wide variety of lipid species, which play a critical role in biological function. Alterations to lipid metabolism can have serious consequences and are observed in viral diseases, particularly those caused by Flaviviridae family viruses. These viruses interfere with lipid metabolism during liver disease, and their pathogenesis involves protein-lipid interactions that affect lipid sorting and metabolism. Molecular dynamics simulations can provide insights into these interactions at the molecular level. This review focuses on recent advancements and knowledge gaps in understanding the molecular mechanisms of lipid-mediated liver disease caused by Flaviviridae viruses, specifically dengue, zika, and hepatitis C.