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 with ¹³C-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.