Adenovirus Reveals New Pathway for Cholesterol Egress from the Endolysosomal System

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.