Cytomegalovirus restructures lipid rafts via a US28/CDC42-mediated pathway, enhancing cholesterol efflux from host cells

Hann Low; Nigora Mukhamedova; Huanhuan L. Cui; Brian P. McSharry; Selmir Avdic; Anh Hoang; Michael Ditiatkovski; Yingying Liu; Ying Fu; Peter J. Meikle; Martin Blomberg; Konstantinos A. Polyzos; William E. Miller; Piotr Religa; Michael Bukrinsky; Cecilia Soderberg-Naucler; Barry Slobedman; Dmitri Sviridov

doi:10.1016/j.celrep.2016.05.070

Cytomegalovirus restructures lipid rafts via a US28/CDC42-mediated pathway, enhancing cholesterol efflux from host cells

Hann Low, Nigora Mukhamedova, Huanhuan L. Cui, Brian P. McSharry, Selmir Avdic, Anh Hoang, Michael Ditiatkovski, Yingying Liu, Ying Fu, Peter J. Meikle, Martin Blomberg, Konstantinos A. Polyzos, William E. Miller, Piotr Religa, Michael Bukrinsky, Cecilia Soderberg-Naucler, Barry Slobedman, Dmitri Sviridov

Dentistry and Medical Sciences

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Abstract

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.

Original language	English
Pages (from-to)	186-200
Number of pages	15
Journal	Cell Reports
Volume	16
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2016.05.070
Publication status	Published - 28 Jun 2016

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10.1016/j.celrep.2016.05.070

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Low, H., Mukhamedova, N., Cui, H. L., McSharry, B. P., Avdic, S., Hoang, A., Ditiatkovski, M., Liu, Y., Fu, Y., Meikle, P. J., Blomberg, M., Polyzos, K. A., Miller, W. E., Religa, P., Bukrinsky, M., Soderberg-Naucler, C., Slobedman, B., & Sviridov, D. (2016). Cytomegalovirus restructures lipid rafts via a US28/CDC42-mediated pathway, enhancing cholesterol efflux from host cells. Cell Reports, 16(1), 186-200. https://doi.org/10.1016/j.celrep.2016.05.070

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title = "Cytomegalovirus restructures lipid rafts via a US28/CDC42-mediated pathway, enhancing cholesterol efflux from host cells",

abstract = "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.",

author = "Hann Low and Nigora Mukhamedova and Cui, {Huanhuan L.} and McSharry, {Brian P.} and Selmir Avdic and Anh Hoang and Michael Ditiatkovski and Yingying Liu and Ying Fu and Meikle, {Peter J.} and Martin Blomberg and Polyzos, {Konstantinos A.} and Miller, {William E.} and Piotr Religa and Michael Bukrinsky and Cecilia Soderberg-Naucler and Barry Slobedman and Dmitri Sviridov",

note = "Publisher Copyright: {\textcopyright} 2016 The Author(s)",

year = "2016",

month = jun,

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doi = "10.1016/j.celrep.2016.05.070",

language = "English",

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Low, H, Mukhamedova, N, Cui, HL, McSharry, BP, Avdic, S, Hoang, A, Ditiatkovski, M, Liu, Y, Fu, Y, Meikle, PJ, Blomberg, M, Polyzos, KA, Miller, WE, Religa, P, Bukrinsky, M, Soderberg-Naucler, C, Slobedman, B & Sviridov, D 2016, 'Cytomegalovirus restructures lipid rafts via a US28/CDC42-mediated pathway, enhancing cholesterol efflux from host cells', Cell Reports, vol. 16, no. 1, pp. 186-200. https://doi.org/10.1016/j.celrep.2016.05.070

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T1 - Cytomegalovirus restructures lipid rafts via a US28/CDC42-mediated pathway, enhancing cholesterol efflux from host cells

AU - Low, Hann

AU - Mukhamedova, Nigora

AU - Cui, Huanhuan L.

AU - McSharry, Brian P.

AU - Avdic, Selmir

AU - Hoang, Anh

AU - Ditiatkovski, Michael

AU - Liu, Yingying

AU - Fu, Ying

AU - Meikle, Peter J.

AU - Blomberg, Martin

AU - Polyzos, Konstantinos A.

AU - Miller, William E.

AU - Religa, Piotr

AU - Bukrinsky, Michael

AU - Soderberg-Naucler, Cecilia

AU - Slobedman, Barry

AU - Sviridov, Dmitri

PY - 2016/6/28

Y1 - 2016/6/28

N2 - 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.

AB - 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.

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JO - Cell Reports

JF - Cell Reports

IS - 1

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Cytomegalovirus restructures lipid rafts via a US28/CDC42-mediated pathway, enhancing cholesterol efflux from host cells

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