Viral effects on metabolism: changes in glucose and glutamine utilization during human cytomegalovirus infection

Abstract

Human cytomegalovirus (HCMV) infection causes dramatic alterations of intermediary metabolism, similar to those found in tumor cells. In infected cells, glucose carbon is not completely broken down by the tricarboxylic acid (TCA) cycle for energy; instead, it is used biosynthetically. This process requires increased glucose uptake, increased glycolysis and the diversion of glucose carbon, in the form of citrate, from the TCA cycle for use in HCMV-induced fatty acid biosynthesis. The diversion of citrate from the TCA cycle (cataplerosis) requires induction of enzymes to promote glutaminolysis, the conversion of glutamine to α-ketoglutarate to maintain the TCA cycle (anaplerosis) and ATP production. Such changes could result in heretofore uncharacterized pathogenesis, potentially implicating HCMV as a subtle cofactor in many maladies, including oncogenesis. Recognition of the effects of HCMV, and other viruses, on host cell metabolism will provide new understanding of viral pathogenesis and novel avenues for antiviral therapy.

Figure 1

Aspects of glucose and glutamine metabolism and fatty acid synthesis. Reactions within the circle occur in the mitochondrion (MITO), while those outside the circle occur in the cytoplasm (CYTO). Movement across the mitochontrial membrane is indicated by dashed arrows. Enzymes and general enzymatic pathways are shown in green. Abbreviations: TCA Cycle, tricarboxylic acid cycle; Glnase, glutaminase; GDH, glutamate dehydrogenase; AcCoA, acetyl coenzyme A; CoA, coenzyme A.

Figure 2

The control of glycolysis by fructose-2,6-bisphosphate. The bifunctional enzyme 6-phosphofructo-2-kinase (PFK-2)/fructose-2,6-bisphosphatase (FBPase-2) can both phosphorylate and dephosphorylate fructose-6-phosphate at the 2 position. A number of kinases (some of which are activated during HCMV infection) can phosphorylate and activate the kinase activity of the enzyme. This increases the levels of fructose-2,6-bisphosphate, which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a key enzyme in glycolytic control. Activation steps are indicated by dashed red arrows.

Figure 3

The enlargement and structural changes in the nucleus and the formation of the assembly compartment during HCMV infection. The two immunofluorescence micrographs show normal nuclei in mock infected cells (left) and the significantly enlarged and kidney shaped nuclei seen in HCMV-infected cells (middle, the nuclei are visualized by staining for lamin B, red). In infected cell nuclei, a perinuclear structure known as the cytoplasmic assembly compartment or assembly complex (AC; visualized by staining for the HCMV tegument protein pp28, green) is seen nestled against the concave surface of the kidney-shaped nucleus ^–. The immunofluorescence micrographs are reproduced from Ref. with permission from the Journal of Virology. As shown in the electron micrograph (right), the AC is made of many vesicular structures; the bar indicates 2 m.

Figure 4

HCMV-mediated modifications in cellular processes that lead to alterations of glucose and glutamine metabolism and fatty acid synthesis. (1) Glucose uptake increases through the induction of the glucose transporter GLUT4 which replaces the transporter GLUT1. (2) Glycolytic enzymes are upregulated and it is likely that glycolysis is allosterically activated by infection. (3) Glucose carbons are diverted from the TCA cycle through transport of citrate from the mitochondrion to the cytoplasm. (4) Fatty acid and sterol synthesis are upregulated so that AcCoA derived from cytoplasmic citrate can be used for fatty acid synthesis. The induction of fatty acid synthesis enzymes and the induction of GLUT4 may be related, as each would occur if HCMV infection induces a form of adipocyte differentiation. (5) Exogenous gutamine uptake is increased in infected cells. (6) Glutaminolysis enzymes are induced to convert the imported glutamine to -ketoglutarate to anapleroetically maintain the TCA cycle. Abbreviations: CYTO, cytoplasm; MITO, mitochondrion.