Cytomegalovirus Restructures Lipid Rafts via a US28/CDC42-Mediated Pathway, Enhancing Cholesterol Efflux from Host Cells

• Published in: Cell reports (Cambridge) 2016-06, Vol.16 (1), p.186-200
• Main Authors: Low, Hann, Mukhamedova, Nigora, Cui, Huanhuan L., McSharry, Brian P., Avdic, Selmir, Hoang, Anh, Ditiatkovski, Michael, Liu, Yingying, Fu, Ying, Meikle, Peter J., Blomberg, Martin, Polyzos, Konstantinos A., Miller, William E., Religa, Piotr, Bukrinsky, Michael, Soderberg-Naucler, Cecilia, Slobedman, Barry, Sviridov, Dmitri
• Format: Article
• Language: English
• Subjects: Animals; Biological Transport; cdc42 GTP-Binding Protein - metabolism; Cholesterol - metabolism; Cytomegalovirus; Cytomegalovirus - metabolism; Cytomegalovirus Infections; Fibroblasts - metabolism; Fibroblasts - pathology; Fibroblasts - virology; Host-Pathogen Interactions; Human cytomegalovirus; Humans; Inflammation - pathology; Lipid Metabolism; Male; Medicin och hälsovetenskap; Membrane Microdomains - metabolism; Membrane Transport Proteins - metabolism; Mice; Mice, Inbred BALB C; Murine cytomegalovirus; RAW 264.7 Cells; Receptors, Chemokine - metabolism; Signal Transduction; Viral Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.05.070

Cytomegalovirus (HCMV) contains cholesterol, but how HCMV interacts with host cholesterol metabolism is unknown. We found that, in human fibroblasts, HCMV infection increased the efflux of cellular cholesterol, despite reducing the abundance of ABCA1. Mechanistically, viral protein US28 was acting through CDC42, rearranging actin microfilaments, causing association of actin with lipid rafts, and leading to a dramatic change in the abundance and/or structure of lipid rafts. These changes displaced ABCA1 from the cell surface but created new binding sites for apolipoprotein A-I, resulting in enhanced cholesterol efflux. The changes also reduced the inflammatory response in macrophages. HCMV infection modified the host lipidome profile and expression of several genes and microRNAs involved in cholesterol metabolism. In mice, murine CMV infection elevated plasma triglycerides but did not affect the level and functionality of high-density lipoprotein. Thus, HCMV, through its protein US28, reorganizes lipid rafts and disturbs cell cholesterol metabolism. [Display omitted] •HCMV modifies lipid rafts through viral protein US28 and host CDC42•Lipid raft modification enhances binding of apoA-I and cholesterol efflux•US28 modifies multiple aspects of host lipid metabolism•Inflammatory response is blunted in US28-transfected macrophages Low et al. find that HCMV, through viral protein US28 and cellular CDC42, rearranges actin microfilaments and modifies lipid rafts to create new binding sites for apolipoprotein A-I on the host plasma membrane. This results in enhanced cellular cholesterol efflux and a reduction in the host inflammatory response.