Interaction of the human cytomegalovirus particle with the host cell induces hypoxia-inducible factor 1 alpha

McFarlane, Steven; Nicholl, Mary Jane; Sutherland, Jane S.; Preston, Chris M.

doi:10.1016/j.virol.2011.03.005

Cited by 34 publications

(31 citation statements)

References 79 publications

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“…In cancer cells, a reduction in mitochondrial metabolism limits production of reactive oxygen species (ROS) and accumulates metabolic intermediates that feed synthesis of nucleotides and fatty acids, features advantageous for rapidly proliferating cells (26,30). A similar metabolic shift has been observed for other nononcogenic DNA viruses (39)(40)(41), with or without HIF-1α stabilization, suggesting that this could be important for viral replication.…”

Section: Discussionmentioning

confidence: 79%

A mechanism for induction of a hypoxic response by vaccinia virus

Mazzon

Peters

Loenarz

et al. 2013

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

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Viruses have evolved sophisticated strategies to exploit host cell function for their benefit. Here we show that under physiologically normal oxygen levels (normoxia) vaccinia virus (VACV) infection leads to a rapid stabilization of hypoxia-inducible factor (HIF)-1α, its translocation into the nucleus and the activation of HIF-responsive genes, such as vascular endothelial growth factor (VEGF), glucose transporter-1, and pyruvate dehydrogenase kinase-1. HIF-1α stabilization is mediated by VACV protein C16 that binds the human oxygen sensing enzyme prolyl-hydroxylase domain containing protein (PHD)2 and thereby inhibits PHD2-dependent hydroxylation of HIF-1α. The binding between C16 and PHD2 is direct and specific, and ectopic expression of C16 alone induces transcription of HIF-1α responsive genes. Conversely, a VACV strain lacking the gene for C16, C16L, is unable to induce HIF-1α stabilization. Interestingly, the N-terminal region of C16 is predicted to have a PHD2-like structural fold but lacks the catalytic active site residues of PHDs. The induction of a hypoxic response by VACV is reminiscent of the biochemical consequences of solid tumor formation, and illustrates a poxvirus strategy for manipulation of cellular gene expression and biochemistry.Orthopoxvirus | variola virus | Warburg effect | glucose metabolism V accinia virus (VACV) is the live vaccine used against smallpox, an extinct human disease caused by variola virus (VARV) (1). VACV and VARV belong to the Orthopoxvirus genus of the Poxviridae, and each have large dsDNA genomes and replicate in the cell cytoplasm (2). VACV can be engineered to express foreign genes and these recombinant viruses have potential as live vaccines against other diseases (3) and are useful laboratory tools, for instance in identifying the target antigens of CD8+ cytotoxic T lymphocytes (4, 5). VACV encodes many genes that are nonessential for virus replication but are important in vivo for defense against the host innate immune system, such as the VACV steroid biosynthetic enzyme 3-β-hydroxysteroid dehydrogenase (6, 7), or for modulation of host cell biochemistry, such as the VACV enzymes thymidine kinase (8), thymidylate kinase (9), and ribonuceotide reductase (10).VACV strain Western Reserve (WR) gene C16L encodes a 37-kDa intracellular protein that contributes to virulence by an unknown mechanism (11). C16 is nonessential for VACV replication, yet orthologs of C16 are conserved in several poxviruses, suggesting an important function (11). VACV also encodes a related protein, C4, with 43% amino acid identity to C16 and that inhibits activation of NF-κB (12).Here a direct interaction is shown between the N-terminal region of C16 and the human oxygen sensor prolyl-hydroxylase domain containing protein (PHD)2. During normoxia, PHD2 is the major enzyme that hydroxylates hypoxia-inducible factor (HIF)-1α on either of two proline residues within the oxygendependent degradation domain (ODD), P402 and P564 (13, 14). After hydroxylation, HIF-1α is ubiquitinated by the von Hippe...

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Section: Discussionmentioning

confidence: 79%

A mechanism for induction of a hypoxic response by vaccinia virus

Mazzon

Peters

Loenarz

et al. 2013

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

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“…McFarlane and colleagues described the ability of HCMV to induce HIF-1 [43], yet the viral proteins and molecular mechanism driving this process remain unclear. To improve our understanding of HCMV-dependent HIF-1 induction, we studied the contribution of US28 to HIF-1 activity upon HCMV infection of relevant cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…This is, partially, attributed to the KSHV-encoded GPCR ORF74 that induces HIF-1 transactivation under non-hypoxic conditions [46, 49]. Other examples of oncogenic viruses increasing HIF-1 activity are Hepatitis B and C virus [51, 52], EBV [53, 54], HPV [55] and HCMV [43]. …”

Section: Discussionmentioning

confidence: 99%

Human cytomegalovirus encoded chemokine receptor US28 activates the HIF-1α/PKM2 axis in glioblastoma cells

et al. 2016

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The human cytomegalovirus (HCMV) encoded chemokine receptor US28 promotes tumorigenesis through activation of various proliferative and angiogenic signaling pathways. Upon infection, US28 displays constitutive activity and signals in a G protein-dependent manner, hijacking the host's cellular machinery. In tumor cells, the hypoxia inducible factor-1α/pyruvate kinase M2 (HIF-1α/PKM2) axis plays an important role by supporting proliferation, angiogenesis and reprogramming of energy metabolism. In this study we show that US28 signaling results in activation of the HIF-1α/PKM2 feedforward loop in fibroblasts and glioblastoma cells. The constitutive activity of US28 increases HIF-1 protein stability through a Gαq-, CaMKII- and Akt/mTOR-dependent mechanism. Furthermore, we found that VEGF and lactate secretion are increased and HIF-1 target genes, glucose transporter type 1 (GLUT1) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), involved in glucose metabolism, are upregulated in US28 expressing cells. In addition, PKM2 is phosphorylated and found to be in a tumor-associated dimeric state upon US28 expression. Also in HCMV-infected cells HIF-1 activity is enhanced, which in part is US28-dependent. Finally, increased proliferation of cells expressing US28 is abolished upon inhibition of the HIF-1α/PKM2 cascade. These data highlight the importance of HIF-1α and PKM2 in US28-induced proliferation, angiogenesis and metabolic reprogramming.

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“…All viruses were used at multiplicities of infection (MOIs) based on their PFU titers in U2OS cells, regardless of the cell type used (54). HCMV strain AD169 was propagated in and titrated on human diploid fibroblasts (HFs) (a gift from Thomas Stamminger), as described previously (55).…”

Section: Viruses and Cellsmentioning

confidence: 99%

Components of Promyelocytic Leukemia Nuclear Bodies (ND10) Act Cooperatively To Repress Herpesvirus Infection

Glaß

Everett

2013

J Virol

102

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Upon the entry of the viral genome into the nucleus, herpes simplex virus type 1 (HSV-1) gene expression is rapidly repressed by constitutively expressed cellular proteins. This intrinsic antiviral defense is normally counteracted by ICP0, which allows virus infection to proceed efficiently. Replication of ICP0-null mutant HSV-1, however, is severely repressed by mechanisms that are conferred, at least in part, by nuclear domain 10 (ND10) components, including hDaxx, the promyelocytic leukemia (PML) protein, and Sp100. To investigate if these ND10 components repress viral gene expression in a cooperative manner, we simultaneously depleted host cells for hDaxx, PML, and Sp100 by multiple short hairpin RNA (shRNA) knockdown from a single lentivirus vector. We found that replication and gene expression of ICP0-null mutant HSV-1 were cooperatively repressed by hDaxx, PML, and Sp100 immediately upon infection, and all stages of virus replication were inhibited. Plaque-forming efficiency was enhanced at least 50-fold in the triple-depleted cells, a much larger increase than achieved by depletion of any single ND10 protein. Similar effects were also observed during infection of triple-depleted cells with human cytomegalovirus (HCMV). Moreover, using a cell culture model of quiescent infection, we found that triple depletion resulted in a much larger number of viral genomes escaping repression. However, triple depletion was unable to fully overcome the ICP0-null phenotype, implying the presence of additional repressive host factors, possibly components of the SUMO modification or DNA repair pathways. We conclude that several ND10 components cooperate in an additive manner to regulate HSV-1 and HCMV infection.

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Interaction of the human cytomegalovirus particle with the host cell induces hypoxia-inducible factor 1 alpha

Cited by 34 publications

References 79 publications

A mechanism for induction of a hypoxic response by vaccinia virus

A mechanism for induction of a hypoxic response by vaccinia virus

Human cytomegalovirus encoded chemokine receptor US28 activates the HIF-1α/PKM2 axis in glioblastoma cells

Components of Promyelocytic Leukemia Nuclear Bodies (ND10) Act Cooperatively To Repress Herpesvirus Infection

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