Cytomegalovirus Restructures Lipid Rafts via a US28/CDC42-Mediated Pathway, Enhancing Cholesterol Efflux from Host Cells.
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.
Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
Hann
H
Low
Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
Nigora
N
Mukhamedova
Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; Department of Medicine, Karolinska Institute, Stockholm 171 76, Sweden.
Huanhuan L
HL
Cui
Discipline of Infectious Diseases and Immunology, University of Sydney, NSW 2006, Australia.
Brian P
BP
McSharry
Discipline of Infectious Diseases and Immunology, University of Sydney, NSW 2006, Australia.
Selmir
S
Avdic
Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
Anh
A
Hoang
Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
Michael
M
Ditiatkovski
Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
Yingying
Y
Liu
Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
Ying
Y
Fu
Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
Peter J
PJ
Meikle
Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
Martin
M
Blomberg
Department of Medicine, Karolinska Institute, Stockholm 171 76, Sweden.
Konstantinos A
KA
Polyzos
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
William E
WE
Miller
Department of Medicine, Karolinska Institute, Stockholm 171 76, Sweden.
Piotr
P
Religa
GW School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA.
Michael
M
Bukrinsky
Department of Medicine, Karolinska Institute, Stockholm 171 76, Sweden.
Cecilia
C
Soderberg-Naucler
Discipline of Infectious Diseases and Immunology, University of Sydney, NSW 2006, Australia.
Barry
B
Slobedman
Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia. Electronic address: dmitri.sviridov@bakeridi.edu.au.
Dmitri
D
Sviridov
D000818:Animals; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D003587:Cytomegalovirus / Q000378:metabolism*; D003586:Cytomegalovirus Infections; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D007249:Inflammation / Q000473:pathology; D050356:Lipid Metabolism; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D000067996:RAW 264.7 Cells; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction; D014764:Viral Proteins / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
D026901:Membrane Transport Proteins; D019707:Receptors, Chemokine; C411191:US28 receptor, Cytomegalovirus; D014764:Viral Proteins; D002784:Cholesterol; D020764:cdc42 GTP-Binding Protein