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.
Highlights
In addition to their vital function in the integrity of biological membranes, lipids play critical roles in multiple cellular functions including energy storage, cell signaling, and intracellular membrane trafficking [1,2]
We have discovered a previously unrecognized pathway for maintaining cholesterol homeostasis that is independent of NPC1 and relies on the interaction between ORP1L on late endosome/lysosome (LE/Lys) and VAPA in endoplasmic reticulum (ER) membranes
The mechanism is novel in that cholesterol transport appears to occur spontaneously as a consequence of acyl-CoA:cholesterol acyltransferase (ACAT)-driven formation of lipid droplets that act as sinks to absorb excess free cholesterol in the ER
Summary
In addition to their vital function in the integrity of biological membranes, lipids play critical roles in multiple cellular functions including energy storage, cell signaling, and intracellular membrane trafficking [1,2]. Multiple positive-strand RNA viruses, including poliovirus, hepatitis C virus, human rhinovirus, Aichi virus, and encephalomyocarditis virus, “hijack” MCSs to induce formation of viral replication complexes (VRCs) [14,15,16,17,18], and the late endosome/lysosome (LE/Lys) membrane protein NPC1 that mediates cholesterol transport to the ER serves as the intracellular receptor for Ebola and Marburg filoviruses [19]. Following a brief discussion of pertinent background information, we describe a novel host–virus interaction regulating cholesterol trafficking at the endosome–ER interface that provides new insights to physiological pathways regulating cholesterol homeostasis
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