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 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.
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Anna
A
Vysochan
Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Arjun
A
Sengupta
Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Aalim M
AM
Weljie
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
James C
JC
Alwine
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; yongjun@mail.med.upenn.edu.|Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Yongjun
0000-0002-4376-8269
Y
Yu
D001275:ATP Citrate (pro-S)-Lyase / Q000235:genetics / Q000378:metabolism*; D000106:Acetate-CoA Ligase / Q000235:genetics / Q000378:metabolism*; D019342:Acetic Acid / Q000378:metabolism*; D000105:Acetyl Coenzyme A / Q000378:metabolism*; D064113:CRISPR-Cas Systems; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000378:metabolism* / Q000821:virology; D003600:Cytosol / Q000378:metabolism; D005347:Fibroblasts; D015971:Gene Expression Regulation, Enzymologic; D055786:Gene Knockout Techniques; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D054884:Host-Pathogen Interactions; D006801:Humans; D050155:Lipogenesis; D008928:Mitochondria / Q000378:metabolism; D061251:Primary Cell Culture; D019289:Pyruvic Acid / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
D034741:RNA, Small Interfering; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D001275:ATP Citrate (pro-S)-Lyase; C000595379:ACSS2 protein, human; D000106:Acetate-CoA Ligase; D005947:Glucose; D019342:Acetic Acid
ACLY; ACSS2; Acetyl-CoA; acetate; human cytomegalovirus