Infection with the hepatitis C virus (HCV) is widespread, and a driving force for many liver diseases. In the cytoplasm, components of the HCV machinery localise to lipid droplets (LDs), which have versatile roles in host–pathogen interaction, cellular trafficking and lipid metabolism. The main regulators of LDs and lipids are proteins from the perilipin (PLIN) family. Now, Eva Herker and co-workers (Lassen et al., 2019) examine the consequences of depleting PLIN2, the main LD coat protein in hepatocytes, on HCV replication and lipid metabolism. The authors find that expression of PLIN2 is needed for efficient HCV particle production. Furthermore, knockdown of PLIN2 leads to an increase in lipolysis rate, preference for excess fatty acid degradation rather than storage, and slightly larger LDs. The authors show that in absence of PLIN2, double membranes surround LDs and HCV-induced vesicular replication organelles. This is likely a consequence of endoplasmic reticulum (ER) cisternae that stay attached to LDs. Importantly, HCV core protein levels decrease at LDs upon PLIN2 loss, and this correlates with fewer and less infectious intracellular and extracellular HCV particles, as well as a reduced secretion of lipoproteins that contain apolipoprotein E (ApoE). Taken together, this study shows that both proper LD structure and trafficking of viral proteins to LDs for virion formation require PLIN2 expression.
