ACSS2-mediated acetyl-CoA synthesis from acetate is necessary for human cytomegalovirus infection

Recent studies have shown that human cytomegalovirus (HCMV) can induce a robust increase in lipid synthesis which is critical for the success of infection. In mammalian cells the central precursor for lipid biosynthesis, cytosolic acetyl CoA (Ac-CoA), is produced by ATP-citrate lyase (ACLY) from mit...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2017-02, Vol.114 (8), p.E1528-E1535
Main Authors: Vysochan, Anna, Sengupta, Arjun, Weljie, Aalim M., Alwine, James C., Yu, Yongjun
Format: Article
Language:English
Subjects:
Biological Sciences
Biosynthesis
Biotechnology
Cytomegalovirus
Herpesviridae
Human cytomegalovirus
Lipids
Mitochondria
PNAS Plus
Viral infections
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Summary:Recent studies have shown that human cytomegalovirus (HCMV) can induce a robust increase in lipid synthesis which is critical for the success of infection. In mammalian cells the central precursor for lipid biosynthesis, cytosolic acetyl CoA (Ac-CoA), is produced by ATP-citrate lyase (ACLY) from mitochondria-derived citrate or by acetyl-CoA synthetase short-chain family member 2 (ACSS2) from acetate. It has been reported that ACLY is the primary enzyme involved in making cytosolic Ac-CoA in cells with abundant nutrients. However, using CRISPR/Cas9 technology, we have shown that ACLY is not essential for HCMV growth and virally induced lipogenesis. Instead, we found that in HCMV-infected cells glucose carbon can be used for lipid synthesis by both ACLY and ACSS2 reactions. Further, the ACSS2 reaction can compensate for the loss of ACLY. However, in ACSS2-KO human fibroblasts both HCMV-induced lipogenesis from glucose and viral growth were sharply reduced. This reduction suggests that glucose-derived acetate is being used to synthesize cytosolic Ac-CoA by ACSS2. Previous studies have not established a mechanism for the production of acetate directly from glucose metabolism. Here we show that HCMV-infected cells produce more glucose-derived pyruvate, which can be converted to acetate through a nonenzymatic mechanism.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1614268114