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Differential Effects of Lipid-lowering Drugs in Modulating Morphology of Cholesterol Particles
Published on: November 10, 2017
Modulation of cell proteome by 25-hydroxycholesterol and 27-hydroxycholesterol: A link between cholesterol metabolism
Andrea Civra1, Mara Colzani2, Valeria Cagno3
1Department of Clinical and Biological Sciences, University of Torino at San Luigi Hospital, Orbassano, Torino, Italy.
Abstract:
Physiological cholesterol metabolism implies the generation of a series of oxidized derivatives, whose oxysterols are by far the most investigated ones for their potential multifaceted involvement in human pathophysiology. In this regard, noteworthy is the broad antiviral activity displayed by defined side chain oxysterols, in particular 25-hydroxycholesterol (25HC) and 27-hydroxycholesterol (27HC). Although their antiviral mechanism(s) may vary depending on virus/host interaction, these oxysterols share the common feature to hamper viral replication by interacting with cellular proteins. Here reported is the first analysis of the modulation of a cell proteome by these two oxysterols, that, besides yielding additional clues about their potential involvement in the regulation of sterol metabolism, provides novelinsights about the mechanism underlying the inhibition of virus entry and trafficking within infected cells. We show here that both 25HC and 27HC can down-regulate the junction adhesion molecule-A (JAM-A) and the cation independent isoform of mannose-6-phosphate receptor (MPRci), two crucial molecules for the replication of all those viruses that exploit adhesion molecules and the endosomal pathway to enter and diffuse within target cells.
Insights
Oxysterols like 25-hydroxycholesterol (25HC) and 27-hydroxycholesterol (27HC) show antiviral activity by affecting cellular proteins. These compounds down-regulate junction adhesion molecule-A (JAM-A) and mannose-6-phosphate receptor (MPRci), inhibiting viral entry.
Area of Science:
- Biochemistry
- Cell Biology
- Virology
Background:
- Cholesterol metabolism generates oxysterols, with potential roles in human pathophysiology.
- Certain oxysterols, specifically 25-hydroxycholesterol (25HC) and 27-hydroxycholesterol (27HC), exhibit significant antiviral properties.
- The antiviral mechanisms of oxysterols involve interactions with cellular proteins, though these can vary based on virus-host interactions.
Purpose of the Study:
- To investigate the impact of 25HC and 27HC on the cell proteome.
- To gain insights into the regulation of sterol metabolism by these oxysterols.
- To elucidate the mechanisms by which these oxysterols inhibit viral entry and intracellular trafficking.
Main Methods:
- Proteomic analysis to identify cellular proteins modulated by 25HC and 27HC.
- Assays to confirm the down-regulation of specific target proteins.
- Investigation of the role of these proteins in viral replication.
Main Results:
- The study presents the first proteome-wide analysis of 25HC and 27HC.
- Both 25HC and 27HC were found to down-regulate junction adhesion molecule-A (JAM-A).
- Both 25HC and 27HC were found to down-regulate the cation-independent mannose-6-phosphate receptor (MPRci).
Conclusions:
- 25HC and 27HC modulate cellular proteomes, offering insights into sterol metabolism.
- The down-regulation of JAM-A and MPRci by these oxysterols is a key mechanism for inhibiting viral entry and spread.
- These findings highlight oxysterols as potential therapeutic agents against viruses utilizing adhesion molecules and endosomal pathways.
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