Activation of cellular metabolism during latent Kaposi's Sarcoma herpesvirus infection

Lagunoff, Michael

doi:10.1016/j.coviro.2016.06.012

Cited by 23 publications

(17 citation statements)

References 34 publications

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“…2c and Supplementary Data 11 ). These enrichments could point to specific metabolic demands of PEL cells, an idea that is supported by an emerging literature on how KSHV reshapes the metabolic status of infected cells 47 .…”

Section: Resultsmentioning

confidence: 84%

Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma

et al. 2018

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Primary effusion lymphoma (PEL) is caused by Kaposi’s sarcoma-associated herpesvirus. Our understanding of PEL is poor and therefore treatment strategies are lacking. To address this need, we conducted genome-wide CRISPR/Cas9 knockout screens in eight PEL cell lines. Integration with data from unrelated cancers identifies 210 genes as PEL-specific oncogenic dependencies. Genetic requirements of PEL cell lines are largely independent of Epstein-Barr virus co-infection. Genes of the NF-κB pathway are individually non-essential. Instead, we demonstrate requirements for IRF4 and MDM2. PEL cell lines depend on cellular cyclin D2 and c-FLIP despite expression of viral homologs. Moreover, PEL cell lines are addicted to high levels of MCL1 expression, which are also evident in PEL tumors. Strong dependencies on cyclin D2 and MCL1 render PEL cell lines highly sensitive to palbociclib and S63845. In summary, this work comprehensively identifies genetic dependencies in PEL cell lines and identifies novel strategies for therapeutic intervention.

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Section: Resultsmentioning

confidence: 84%

Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma

et al. 2018

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“…Many diverse viruses induce changes in the metabolic activity of their host cells (reviewed in (16)(17)(18)(19)(47)(48)(49)(50)). Like HCMV, infection with Kaposi's sarcoma-associated virus (KSHV) increases FA synthesis (51,52).…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus pUL37x1 Is Important for Remodeling of Host Lipid Metabolism

Harwood

Wise

et al. 2019

J Virol

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Human cytomegalovirus (HCMV) replication requires host metabolism. Infection alters the activity in multiple metabolic pathways, including increasing fatty acid elongation and lipid synthesis. The virus-host interactions regulating the metabolic changes associated with replication are essential for infection. While multiple host factors, including kinases and transcription factors, important for metabolic changes that occur following HCMV infection have been identified, little is known about the viral factors required to alter metabolism. In this study, we tested the hypothesis that pUL37x1 is important for the metabolic remodeling that is necessary for HCMV replication using a combination of metabolomics, lipidomics, and metabolic tracers to measure fatty acid elongation. We observed that fibroblast cells infected with wild-type (WT) HCMV had levels of metabolites similar to those in cells infected with a mutant virus lacking the UL37x1 gene, subUL37x1. However, we found that relative to WT-infected cells, subUL37x1-infected cells had reduced levels of two host proteins that were previously demonstrated to be important for lipid metabolism during HCMV infection: fatty acid elongase 7 (ELOVL7) and the endoplasmic reticulum (ER) stress-related kinase PERK. Moreover, we observed that HCMV infection results in an increase in phospholipids with very-long-chain fatty acid tails (PL-VLCFAs) that contain 26 or more carbons in one of their two tails. The levels of many PL-VLCFAs were lower in subUL37x1-infected cells than in WT-infected cells. Overall, we conclude that although pUL37x1 is not necessary for network-wide metabolic changes associated with HCMV infection, it is important for the remodeling of a subset of metabolic changes that occur during infection. IMPORTANCE Human cytomegalovirus (HCMV) is a common pathogen that asymptomatically infects most people and establishes a lifelong infection. However, HCMV can cause end-organ disease that results in death in the immunosuppressed and is a leading cause of birth defects. HCMV infection depends on host metabolism, including lipid metabolism. However, the viral mechanisms for remodeling of metabolism are poorly understood. In this study, we demonstrate that the viral UL37x1 protein (pUL37x1) is important for infection-associated increases in lipid metabolism, including fatty acid elongation to produce very-long-chain fatty acids (VLCFAs). Furthermore, we found that HCMV infection results in a significant increase in phospholipids, particularly those with VLCFA tails (PL-VLCFAs). We found that pUL37x1 was important for the high levels of fatty acid elongation and PL-VLCFA accumulation that occur in HCMV-infected cells. Our findings identify a viral protein that is important for changes in lipid metabolism that occur following HCMV infection.

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“…The induction of fatty acid synthesis and glycolysis, which represents the main source of ATP in cancer endothelial cells, is also believed to be involved in mechanisms related to energy production and cell-membrane morphogenesis, as well as cell growth stimulation and maintenance of the division rate [56,57]. More specifically, HHV8 latent infection has been reported as being characterized by the Warburg effect, which is a typical metabolic alteration in tumour cells consisting of the enhancement of aerobic glycolysis, an increase in the production of lactic acid and a consequent reduction of oxidative phosphorylation [17,58,59]. This phenomenon, which is common to most cancer cells, seems to be necessary for tumour transformation and malignant cell survival, as well as for HHV8 latency and oncogenesis in permissive cells, such as the endothelial ones which are the most relevant in KS lesions.…”

Section: Endothelial Cells: Glycolysis Warburg Effect and Oncogenesismentioning

confidence: 99%

Human Herpesvirus 8 and Host-Cell Interaction: Long-Lasting Physiological Modifications, Inflammation and Related Chronic Diseases

2020

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Oncogenic and latent-persistent viruses belonging to both DNA and RNA groups are known to cause serious metabolism alterations. Among these, the Human Herpesvirus 8 (HHV8) infection induces stable modifications in biochemistry and cellular metabolism, which in turn affect its own pathological properties. HHV8 enhances the expression of insulin receptors, supports the accumulation of neutral lipids in cytoplasmic lipid droplets and induces alterations in both triglycerides and cholesterol metabolism in endothelial cells. In addition, HHV8 is also known to modify immune response and cytokine production with implications for cell oxidative status (i.e., reactive oxygen species activation). This review underlines the recent findings regarding the role of latent and persistent HHV8 viral infection in host physiology and pathogenesis.

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Activation of cellular metabolism during latent Kaposi's Sarcoma herpesvirus infection

Cited by 23 publications

References 34 publications

Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma

Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma

Human Cytomegalovirus pUL37x1 Is Important for Remodeling of Host Lipid Metabolism

Human Herpesvirus 8 and Host-Cell Interaction: Long-Lasting Physiological Modifications, Inflammation and Related Chronic Diseases

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