Adenovirus Reveals New Pathway for Cholesterol Egress from the Endolysosomal System

Abstract

In addition to providing invaluable insights to the host response to viral infection, adenovirus continues to be an important model system for discovering basic aspects of cell biology. This is especially true for products of early region three (E3), which have provided the foundation for understanding many new mechanisms regulating intracellular trafficking of host cell proteins involved in the host immune response. Cholesterol homeostasis is vital for proper cellular physiology, and disturbances in cholesterol balance are increasingly recognized as important factors in human disease. Despite its central role in numerous aspects of cellular functions, the mechanisms responsible for delivery of dietary cholesterol to the endoplasmic reticulum, where the lipid metabolic and regulatory machinery reside, remain poorly understood. In this review, we describe a novel intracellular pathway for cholesterol trafficking that has been co-opted by an adenovirus E3 gene product. We describe what is known about the molecular regulation of this pathway, how it might benefit viral replication, and its potential involvement in normal cell physiology. Finally, we make a case that adenovirus has co-opted a cellular pathway that may be dysregulated in various human diseases.

Multifaceted Nature of Lipid Droplets in Viral Interactions and Pathogenesis

“…In this case, enteroids have been cultured and infected with rotavirus, and it was observed that the infection by this virus induces an exacerbation of lipid droplets. It was confirmed that the virus takes advantage of the lipogenesis pathways and lipid droplets as structural platforms for virus replication [ 126 ].…”

“…This has been correlated with elevated levels of total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL). This was observed when analyzing serum from AD-5 seropositive individuals using an automated biochemical analyzer and flow cytometry; however, triacylglycerol levels in monocytes derived from AD-5 seropositive individuals were lower compared to control monocytes from AD-5 seronegative individuals [ 27 , 126 ]. This increase in lipoproteins led to an increase in reactive oxygen species (ROS) in addition to activating the innate immune response observed by elevated levels of interleukins and interferons which activated potent antiviral inflammatory responses.…”

“…This increase in lipoproteins led to an increase in reactive oxygen species (ROS) in addition to activating the innate immune response observed by elevated levels of interleukins and interferons which activated potent antiviral inflammatory responses. Some studies mention that the immunometabolism which includes changes in lipid metabolism may possibly be associated with the development of cancer; however, it requires further study to determine if the changes produced by infections by this virus and lipid droplets can trigger oncogenic events [ 126 ].…”

Coordination of inter-organelle communication and lipid fluxes by OSBP-related proteins

“…We had earlier reported that overexpression of human ORP1L in macrophages enhanced atherogenesis in LDL-receptor deficient mice and inhibited macrophage cholesterol efflux [140], consistent with a function of ORP1L in cholesterol trafficking in vivo. Carlin and Manor [141] suggested the intriguing scenario that ORP1L could represent an alternative, under normal conditions tightly regulated cholesterol transport machinery, co-opted upon specific pathologic situations. Examples of this are the endo-lysosomal lipid accumulation upon adenoviral infection that is mitigated by the RIDα-ORP1L route [142], and foam cell formation characterized by excessive cholesterol ester synthesis and storage e.g.…”

“…involves the adenoviral protein RIDa encoded by the early region E3 transcript. This protein attenuates EGFR signalling and dampens pro-inflammatory NF-kB activity induced by the stressactivated EGFR signalling during viral entry [141]. In cells infected with RIDa mutant virus, an NPClike endo-lysosomal lipid storage phenotype arises [142], suggesting that RIDa is required to maintain a normal cholesterol distribution in the infected cells.…”