Human Adenoviruses, Cholesterol Trafficking, and NF-κB Signaling.

The interplay between viruses and host factors regulating inflammatory or cytotoxic responses directed against infected cells is well documented. Viruses have evolved a wide array of mechanisms that strike a balance between the elimination of virus and immune-mediated tissue injury by antiviral immune responses. The topic of this mini-review is a series of recent studies demonstrating a link between cholesterol trafficking and innate immune responses in cells infected with human adenoviruses that provide the backbone of commonly used vectors in gene medicine.

Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum.

Human adenoviruses (Ads) generally cause mild self-limiting infections but can lead to serious disease and even be fatal in high-risk individuals, underscoring the importance of understanding how the virus counteracts host defense mechanisms. This study had two goals. First, we wished to determine the molecular basis of cholesterol homeostatic responses induced by the early region 3 membrane protein RIDα via its direct interaction with the sterol-binding protein ORP1L, a member of the evolutionarily conserved family of oxysterol-binding protein (OSBP)-related proteins (ORPs).

Adenovirus RIDα uncovers a novel pathway requiring ORP1L for lipid droplet formation independent of NPC1.

Niemann-Pick disease type C (NPC) is caused by mutations in NPC1 or NPC2, which coordinate egress of low-density-lipoprotein (LDL)-cholesterol from late endosomes. We previously reported that the adenovirus-encoded protein RIDα rescues the cholesterol storage phenotype in NPC1-mutant fibroblasts. We show here that RIDα reconstitutes deficient endosome-to-endoplasmic reticulum (ER) transport, allowing excess LDL-cholesterol to be esterified by acyl-CoA:cholesterol acyltransferase and stored in lipid droplets (LDs) in NPC1-deficient cells.

Molecular pathways for intracellular cholesterol accumulation: common pathogenic mechanisms in Niemann-Pick disease Type C and cystic fibrosis.

It has been less than two decades since the underlying genetic defects in Niemann-Pick disease Type C were first identified. These defects impair function of two proteins with a direct role in lipid trafficking, resulting in deposition of free cholesterol within late endosomal compartments and a multitude of effects on cell function and clinical manifestations. The rapid pace of research in this area has vastly improved our overall understanding of intracellular cholesterol homeostasis.

Autosomal recessive polycystic kidney disease epithelial cell model reveals multiple basolateral epidermal growth factor receptor sorting pathways.

Sorting and maintenance of the EGF receptor on the basolateral surface of renal epithelial cells is perturbed in polycystic kidney disease and apical expression of receptors contributes to severity of disease. The goal of these studies was to understand the molecular basis for EGF receptor missorting using a well-established mouse model for the autosomal recessive form of the disease. We have discovered that multiple basolateral pathways mediate EGF receptor sorting in renal epithelial cells.

Adenovirus RID-alpha activates an autonomous cholesterol regulatory mechanism that rescues defects linked to Niemann-Pick disease type C.

Host-pathogen interactions are important model systems for understanding fundamental cell biological processes. In this study, we describe a cholesterol-trafficking pathway induced by the adenovirus membrane protein RID-alpha that also subverts the cellular autophagy pathway during early stages of an acute infection. A palmitoylation-defective RID-alpha mutant deregulates cholesterol homeostasis and elicits lysosomal storage abnormalities similar to mutations associated with Niemann-Pick type C (NPC) disease.

Adenovirus RIDalpha regulates endosome maturation by mimicking GTP-Rab7.

The small guanosine triphosphatase Rab7 regulates late endocytic trafficking. Rab7-interacting lysosomal protein (RILP) and oxysterol-binding protein-related protein 1L (ORP1L) are guanosine triphosphate (GTP)-Rab7 effectors that instigate minus end-directed microtubule transport. We demonstrate that RILP and ORP1L both interact with the group C adenovirus protein known as receptor internalization and degradation alpha (RIDalpha), which was previously shown to clear the cell surface of several membrane proteins, including the epidermal growth factor receptor and Fas (Carlin, C.

A tyrosine-based signal plays a critical role in the targeting and function of adenovirus RIDalpha protein.

Early region 3 genes of human adenoviruses contribute to the virus life cycle by altering the trafficking of cellular proteins involved in adaptive immunity and inflammatory responses. The ability of early region 3 genes to target specific molecules suggests that they could be used to curtail pathological processes associated with these molecules and treat human disease. However, this approach requires genetic dissection of the multiple functions attributed to early region 3 genes.