1. AMPK is activated by HCMV; inhibition of the kinase blocks the glycolytic activation that is normally induced by infection and markedly reduces the production of infectious progeny. Whereas the induction of glycolysis enhances the production of HCMV progeny, AMPK activity also could have negative effects on viral replication given that the kinase phosphorylates and inhibits the activity of acetyl CoA carboxylase 1 (ACC1), which is required for fatty acid biosynthesis, and 3-hydroxy-3-methylglutaryl (HMG) CoA reductase, which plays a key role in cholesterol biosynthesis. Both of these enzymes are required for optimal production of HCMV progeny, so the virus apparently protects these two activities after AMPK has been activated.
AMPK is activated by HCMV; inhibition of the kinase blocks the glycolytic activation that is normally induced by infection and markedly reduces the production of infectious progeny. Whereas the induction of glycolysis enhances the production of HCMV progeny, AMPK activity also could have negative effects on viral replication given that the kinase phosphorylates and inhibits the activity of acetyl CoA carboxylase 1 (ACC1), which is required for fatty acid biosynthesis, and 3-hydroxy-3-methylglutaryl (HMG) CoA reductase, which plays a key role in cholesterol biosynthesis. Both of these enzymes are required for optimal production of HCMV progeny, so the virus apparently protects these two activities after AMPK has been activated.
It is critically important for HCMV to maintain mTORC1 activity throughout the infectious cycle—not only for the transport of SREBP1 to the nucleus, but also for the maintenance of glycolysis and translation and the inhibition of autophagy.
HCMV infection activates the ChREBPs, transcription factors that activate genes whose products increase glucose uptake, glycolysis, the pentose phosphate pathway, and fatty acid and cholesterol synthesis.
The unfolded protein response sensor PERK is increased and activated during infection. However, its effects are highly controlled in the infected cell. One function that is maintained is lowering the level of the Insig1 protein. This is instrumental in initiating SREBP1 activation through processing and nuclear import. SREBP1 activates the transcription of genes encoding enzymes for fatty acid synthesis.
The export of citrate from the mitochondrion is increased during HCMV infection in order to supply cytoplasmic acetyl CoA for fatty acid synthesis. How this is achieved is yet to be determined.
The unfolded protein response is activated during HCMV infection, but the consequences of this activation are highly controlled in the infected cells, such that aspects deleterious to infection are inhibited and aspects beneficial to infection are maintained.
The unfolded protein response is activated during HCMV infection, but the consequences of this activation are highly controlled in the infected cells, such that aspects deleterious to infection are inhibited and aspects beneficial to infection are maintained.
HCMV induces the uptake of exogenous glutamine via the glutamine transporter and increases the expression and activity of glutaminase and glutamate dehydrogenase, the enzymes needed to convert glutamine to α-ketoglutarate. This process, called glutamine anaplerosis, maintains the tricarboxylic acid cycle when citrate is removed to the cytoplasm.
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