Saturated Very Long Chain Fatty Acids Are Required for the Production of Infectious Human Cytomegalovirus Progeny

PLoS Pathogens

Joshua D. Rabinowitz¹  John G. Purdy¹  Emre Koyuncu²  Thomas Shenk² 

[1] Department of Chemistry and Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America;Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America

关键词: Fatty acids;    Small interfering RNAs;    Virions;    Viral replication;    Lipids;    Enzyme metabolism;    Fibroblasts;    Cell metabolism;   

DOI  :  10.1371/journal.ppat.1003333

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Human cytomegalovirus hijacks host cell metabolism, increasing the flux of carbon from glucose to malonyl-CoA, the committed precursor to fatty acid synthesis and elongation. Inhibition of acetyl-CoA carboxylase blocks the production of progeny virus. To probe further the role of fatty acid metabolism during infection, we performed an siRNA screen to identify host cell metabolic enzymes needed for the production of infectious cytomegalovirus progeny. The screen predicted that multiple long chain acyl-CoA synthetases and fatty acid elongases are needed during infection, and the levels of RNAs encoding several of these enzymes were upregulated by the virus. Roles for acyl-CoA synthetases and elongases during infection were confirmed by using small molecule antagonists. Consistent with a role for these enzymes, mass spectrometry-based fatty acid analysis with13C-labeling revealed that malonyl-CoA is consumed by elongases to produce very long chain fatty acids, generating an approximately 8-fold increase in C26-C34 fatty acid tails in infected cells. The virion envelope was yet further enriched in C26-C34 saturated fatty acids, and elongase inhibitors caused the production of virions with lower levels of these fatty acids and markedly reduced infectivity. These results reveal a dependence of cytomegalovirus on very long chain fatty acid metabolism.

【 授权许可】

CC BY