Human Cytomegalovirus Activates Glucose Transporter 4 Expression To Increase Glucose Uptake during Infection

Yu, Yongjun; Maguire, Tobi G.; Alwine, James C.

doi:10.1128/jvi.01967-10

Cited by 140 publications

(163 citation statements)

References 45 publications

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“…This possibility is reinforced by the requirement for CaMKK, an AMPK activator, to generate optimal yields of HCMV (Fig. 2 B and C) and to elevate glycolysis after infection (11).…”

Section: Discussionmentioning

confidence: 99%

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Human kinome profiling identifies a requirement for AMP-activated protein kinase during human cytomegalovirus infection

Terry¹,

Vastag

Rabinowitz

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Human cytomegalovirus (HCMV) modulates numerous cellular signaling pathways. Alterations in signaling are evident from the broad changes in cellular phosphorylation that occur during HCMV infection and from the altered activity of multiple kinases. Here we report a comprehensive RNAi screen, which predicts that 106 cellular kinases influence growth of the virus, most of which were not previously linked to HCMV replication. Multiple elements of the AMP-activated protein kinase (AMPK) pathway scored in the screen. As a regulator of carbon and nucleotide metabolism, AMPK is poised to activate many of the metabolic pathways induced by HCMV infection. An AMPK inhibitor, compound C, blocked a substantial portion of HCMV-induced metabolic changes, inhibited the accumulation of all HCMV proteins tested, and markedly reduced the production of infectious progeny. We propose that HCMV requires AMPK or related activity for viral replication and reprogramming of cellular metabolism.herpesvirus | siRNA V iruses are dependent on host cell signaling pathways for replication and spread. Infection with the prevalent β-herpes virus human cytomegalovirus (HCMV) induces increased levels of protein phosphorylation and markedly alters host cell signal transduction pathways (1). A portion of the phosphorylation changes induced by HCMV infection are attributed to the Ser/ Thr kinase encoded by the viral genome, pUL97 (2), and others may derive from cellular kinase(s) packaged into virions (3) or from cellular kinases known to be activated by HCMV (4).Here we sought to more completely delineate the effects of HCMV infection on kinase signaling by performing an siRNA screen of the entire cellular kinome. The screen identified 106 kinases predicted to influence the production of virus. The hits included the 5′-AMP-activated protein kinase (AMPK), a sensor of cellular energy homeostasis. AMPK is composed of three subunits: a catalytic subunit, AMPKα, and two regulatory subunits, AMPKβ and AMPKγ. Activation of the kinase requires cooperative AMP binding to AMPKγ, which occurs stochastically with shifts in the AMP:ATP ratio, and phosphorylation of AMPKα at Thr172 (5, 6). At least three different kinases are reported to phosphorylate Thr172 of AMPKα: Ca 2+ /calmodulindependent kinase kinase (CaMKK), TGF-β-activated kinase 1 (TAK1), and liver kinase B1 (LKB1) (7). Activated AMPK phosphorylates a number of substrates to effect changes in central carbon metabolism, lipid metabolism, physiological homeostasis, cell growth, apoptosis, and gene expression (5).HCMV induces glycolysis (8-10) and also causes increased levels of the glucose transporter GLUT4 at the plasma membrane increasing glucose uptake (11).AMPK controls GLUT4 relocalization to the plasma membrane (5), and this regulation likely links the kinase to altered metabolism in HCMV-infected cells. However, previous work indicates that pharmacological activation of AMPK during the early phase of HCMV infection can be deleterious to viral replication (12), yet CaMKK activity is required for ...

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“…This possibility is reinforced by the requirement for CaMKK, an AMPK activator, to generate optimal yields of HCMV (Fig. 2 B and C) and to elevate glycolysis after infection (11).…”

Section: Discussionmentioning

confidence: 99%

“…HCMV induces glycolysis (8)(9)(10) and also causes increased levels of the glucose transporter GLUT4 at the plasma membrane increasing glucose uptake (11).…”

mentioning

confidence: 99%

Human kinome profiling identifies a requirement for AMP-activated protein kinase during human cytomegalovirus infection

Terry¹,

Vastag

Rabinowitz

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…This and other unsaturated and monounsaturated PAs induced during infection (Dataset S1) could accumulate in part through phospholipase D hydrolysis of PC (33), and likely have signaling roles (32). For example, unsaturated PAs can induce MAPK activity (34), and p38 MAPK is induced during HCMV infection in two waves, one of which seems to coincide with the elevation of PAs (35); and the interaction of PA with glucose transporter 4 (GLUT4) (36) could facilitate the massive induction in activity of this glucose transporter after infection (37). PA (38:4) was the only species identified in virions, and it was also elevated in infected relative to mock-infected cells.…”

Section: Discussionmentioning

confidence: 99%

Synaptic vesicle-like lipidome of human cytomegalovirus virions reveals a role for SNARE machinery in virion egress

Liu¹,

Sharon-Friling²,

Ivanova

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Human cytomegalovirus induces and requires fatty acid synthesis. This suggests an essential role for lipidome remodeling in viral replication. We used mass spectrometry to quantify glycerophospholipids in mock-infected and virus-infected fibroblasts, as well as in virions. Although the lipid composition of mock-infected and virus-infected fibroblasts was similar, virions were markedly different. The virion envelope contained twofold more phosphatidylethanolamines and threefold less phosphatidylserines than the host cell. This indicates that the virus buds from a membrane with a different lipid composition from the host cell as a whole. Compared with published datasets, the virion envelope showed the greatest similarity to the synaptic vesicle lipidome. Synaptosomeassociated protein of 25 kDa (SNAP-25) is a component of the complex that mediates exocytosis of synaptic vesicles in neurons; and its homolog, SNAP-23, functions in exocytosis in many other cell types. Infection induced the relocation of SNAP-23 to the cytoplasmic viral assembly zone, and knockdown of SNAP-23 inhibited the production of virus. We propose that cytomegalovirus capsids acquire their envelope by budding into vesicles with a lipid composition similar to that of synaptic vesicles, which subsequently fuse with the plasma membrane to release virions from the cell.H uman cytomegalovirus (HCMV) is a member of the enveloped herpesvirus family. It is a widespread pathogen that can cause disease in immunologically immature or compromised individuals (1). HCMV infection substantially alters the metabolism of cultured fibroblasts (2), inducing a marked increase in the flux of carbon from glucose into fatty acids (3). Consistent with the enhanced flux, inhibition of acetyl-CoA carboxylase, the first committed enzyme in the fatty acid biosynthetic pathway, reduces the yield of infectious virus. Thus, lipid synthesis is required during the HCMV replication cycle. Newly synthesized membranes likely accumulate in the assembly compartment (4-8), a virus-induced organelle with virus-coded proteins and cellular proteins that include markers of the exocytic and endocytic networks. This is the site at which viral capsids acquire an envelope (9-12).Glycerophospholipids are major components of cellular membranes. This family of lipids consists of a glycerol backbone, a functional head group, and two fatty acids of varying length and unsaturation. Phosphatidic acid (PA) serves as the basic glycerophospholipid building block, with its phosphate group esterified to a head group to produce phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylglycerol (PG), or diphosphatidylglycerol. By using mass spectrometry, it is possible to identify and quantify numerous glycerolphospholipid species, differing in head group, acyl chain length, and degree of unsaturation (13-16). This quantitative lipidomics approach has been used to generate detailed descriptions of several viral envelopes, including those acqui...

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“…The first immune responders to bacterial infection, neutrophils, rely on glucose and glycolysis for key effector functions, including the formation of neutrophil extracellular traps (67)(68)(69). Viral infection may also lead to decreased glucose availability for infiltrating immune cells due to the infiltration of immune cells and the fact that virally infected cells increase glucose uptake to facilitate viral replication (70)(71)(72)(73)(74)(75). Virally infected cells also increase the uptake of other nutrients, including the amino acid glutamine (74,76), which is important for effector T cell responses (77).…”

Section: Oxphos Facilitates Cellular Longevitymentioning

confidence: 99%

Metabolic regulation of immune responses: therapeutic opportunities

Aßmann¹,

Finlay²

2016

Journal of Clinical Investigation

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Human Cytomegalovirus Activates Glucose Transporter 4 Expression To Increase Glucose Uptake during Infection

Cited by 140 publications

References 45 publications

Human kinome profiling identifies a requirement for AMP-activated protein kinase during human cytomegalovirus infection

Human kinome profiling identifies a requirement for AMP-activated protein kinase during human cytomegalovirus infection

Synaptic vesicle-like lipidome of human cytomegalovirus virions reveals a role for SNARE machinery in virion egress

Metabolic regulation of immune responses: therapeutic opportunities

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