Faculty Collaboration Database

Low-Density Lipoprotein Receptor Suppresses the Endogenous Cholesterol Synthesis Pathway To Oppose Gammaherpesvirus Replication in Primary Macrophages. J Virol 2021 Aug 10;95(17):e0064921

Date

06/10/2021

Pubmed ID

34105999

Pubmed Central ID

PMC8354329

DOI

10.1128/JVI.00649-21

Scopus ID

2-s2.0-85112335753 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

Gammaherpesviruses are ubiquitous pathogens that establish lifelong infections in >95% of adults worldwide and are associated with several cancers. We have shown that endogenous cholesterol synthesis supports gammaherpesvirus replication. However, the role of exogenous cholesterol exchange and signaling during infection remains poorly understood. Extracellular cholesterol is carried in the serum by several lipoproteins, including low-density lipoproteins (LDL). The LDL receptor (LDL-R) mediates the endocytosis of these cholesterol-rich LDL particles into the cell, thereby supplying the cell with cholesterol. We found that LDL-R expression attenuates gammaherpesvirus replication during the early stages of the replication cycle, as evident by increased viral gene expression in LDL-R^-/- primary macrophages. This was not observed in primary fibroblasts, indicating that the antiviral effects of LDL-R are cell type specific. Increased viral gene expression in LDL-R^-/- primary macrophages was due to increased activity of the endogenous cholesterol synthesis pathway. Intriguingly, despite type I interferon-driven increase in LDL-R mRNA levels in infected macrophages, protein levels of LDL-R continually decreased over the single cycle of viral replication. Thus, our study has uncovered an intriguing tug of war between the LDL-R-driven antiviral effect on cholesterol metabolism and the viral targeting of the LDL-R protein. IMPORTANCE LDL-R is a cell surface receptor that mediates the endocytosis of cholesterol-rich low-density lipoproteins, allowing cells to acquire cholesterol exogenously. Several RNA viruses usurp LDL-R function to facilitate replication; however, the role of LDL-R in DNA virus infection remains unknown. Gammaherpesviruses are double-stranded DNA viruses that are associated with several cancers. Here, we show that LDL-R attenuates gammaherpesvirus replication in primary macrophages by decreasing endogenous cholesterol synthesis activity, a pathway known to support gammaherpesvirus replication. In response, LDL-R protein levels are decreased in infected cells to mitigate the antiviral effects, revealing an intriguing tug of war between the virus and the host.

Author List

Aurubin CA, Knaack DA, Sahoo D, Tarakanova VL

Authors

Daisy Sahoo PhD Dean, Professor in the Medicine department at Medical College of Wisconsin
Vera Tarakanova PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cholesterol
Female
Gammaherpesvirinae
Herpesviridae Infections
Host-Pathogen Interactions
Interferon Type I
Lipogenesis
Macrophages
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptors, LDL
Signal Transduction
Virus Replication