Dr. Alwine studies how DNA viruses deal with the consequences of inducing cellular stress responses. During infection by human cytomegalovirus (HCMV; a herpesvirus) and simian virus 40 (SV40), cellular stress responses are triggered due to the impact of the viral infection on the cell, for example, the stress resulting from the greatly increased metabolic activity needed for successful viral replication. Stress responses may be induced due to nutrient deprivation, hypoxia or the induction of the unfolded protein response (UPR, a form of endoplasmic reticulum stress). Stress responses are normally activated when the cell is in distress, and are designed to slow down cellular processes to allow the cell to recover. For example, a major effect of most stress responses is the inhibition of protein synthesis, and if recovery is impossible, the stress responses can lead to apoptosis. Inhibition of translation and apoptosis are severe disadvantages to the replicating DNA virus. Thus viruses have evolved mechanisms to circumvent stress responses, or modify them so that they are advantageous to the viruses.
Current projects in the lab include studies of:
-how HCMV maintains mTOR kinase activity during periods of cellular stress.
-how translational mechanisms are altered in HCMV infected cells to circumvent inhibition of viral protein translation during infection.
-how glucose and glutamine uptake and utilization are altered in HCMV infected cells to accommodate the needs of the viral infection and how this relates to a potential role of HCMV in oncogenesis.
-how UPR factors are employed by the virus to alter metabolism and to mediate viral egress and assembly.
Dr. Alwine's work has shown that HCMV and SV40 induce mechanisms which circumvent the inhibitory effects of the stress responses. Examining viral effects on translational controls, his laboratory has shown that during SV40 and HCMV infections the activities of cellular kinases such as PI3K/Akt, mTOR, and the signaling pathways of the UPR are significantly altered in ways that are advantageous for viral replication. This results in the maintenance of both global and cap-dependent translation even under conditions in which they would normally be inhibited by stress responses. In recent studies Dr. Alwine’s lab has shown that HCMV uses components of stress responses to affect alteration in cellular metabolism, specifically changes in the way cells utilize glucose and glutamine which is similar to the way metabolism is altered in tumor cells.
How does this relate to cancer? The many interactions that HCMV has with signaling and stress response pathways provide a means for vast effects on cellular physiology. The resulting pathogenic effects could implicate HCMV as a subtle, and unexpected, cofactor in many maladies. Many of the HCMV-induced changes that we see in signaling pathways and cellular metabolism are similar to those that occur during tumorigenesis. Although HCMV is generally not regarded to be an oncogenic virus, HCMV infection has been implicated in malignant diseases. On the basis of these and other findings it has been proposed that HCMV may be an oncomodulator. This suggests that HCMV may infect tumor cells and increase their malignancy by affecting stress response signaling and cellular metabolism. Viruses have long served as a means to study and decipher complex cellular phenomena. The understanding of how viruses manipulate key signaling pathways and alter metabolism will provide valuable insight into not only how viruses manipulate these pathways, resulting in pathogenesis, but also the normal cellular controls of these pathways which may arise under special growth and metabolic conditions.
01. Buchkovich NJ, Yu Y, Zampieri CA, Alwine JC. The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K-Akt-mTOR signalling pathway. Nature Reviews: Microbiology 6(4):266-75. 6(4):266-75. Review. 2008. PubMed PMID: 18311165; PubMed Central PMCID: PMC2597498.
02. Chambers JW, Maguire TG, Alwine JC. Glutamine metabolism is essential for human cytomegalovirus infection. Journal of Virology 84(4):1867-73. 2009. PubMed PMID: 19939921; PubMed Central PMCID: PMC2812398.
03. Buchkovich NJ, Maguire TG, Alwine JC. Role of the endoplasmic reticulum chaperone BiP, SUN domain proteins, and dynein in altering nuclear morphology during human cytomegalovirus infection. Journal of Virology 84(14):7005-17. 2010. PubMed PMID: 20484513.
04. Buchkovich NJ, Yu Y, Pierciey FJ Jr, Alwine JC. Human Cytomegalovirus Induces the Endoplasmic Reticulum Chaperone BiP through Increased Transcription and Activation of Translation by Using the BiP Internal Ribosome Entry Site. J. Virol. 84: 11479-11486. 2010. PMID: 20739513
05. Yu Y, Maguire TG, Alwine JC. Human Cytomegalovirus Activates Glucose Transporter 4 Expression to Increase Glucose Uptake during Infection. Journal of Virology 85 (4):1573-1580, 2011. PMID: 21147915; PMCID: PMC2953172.
05: Buchkovich NJ, Maguire TG, Yu Y, Paton AW, Paton JC, Alwine JC. Human cytomegalovirus specifically controls the levels of the endoplasmic reticulum chaperone BiP/GRP78, which is required for virion assembly. Journal of Virology 82(1):31-9. 2008. PubMed PMID: 17942541; PubMed Central PMCID: PMC2224369.
06. Clippinger AJ, Maguire TG, Alwine JC. The changing role of mTOR kinase in the maintenance of protein synthesis during human cytomegalovirus infection. J Virol. 85(8):3930-9. 2011. PMID: 21307192; PMCID: PMC3126115.
07. Clippinger AJ, Maguire TG, Alwine JC. Human cytomegalovirus infection maintains mTOR activity and its perinuclear localization during amino acid deprivation. J Virol.85(18):9369-76. 2011. PMID: 1734039; PMCID: PMC3165763
08. Yu Y, Maguire TG, Alwine JC. Human cytomegalovirus infection induces adipocyte-like lipogenesis through activation of sterol regulatory element binding protein 1. J Virol. 86(6):2942-9. 2012. PMID: 22258239; PMCID: PMC3302344
09. Clippinger AJ, Alwine JC. Dynein mediates the localization and activation of mTOR in normal and human cytomegalovirus-infected cells. Genes Dev. 26(18):2015-26. 2012. PMID: 2987636; PMCID: PMC3444728.
10. Alwine JC. DNA Viruses and Cancer: Taking a Broader Look , in “Cancer Associated Viruses”, Series “Current Cancer Research” pp. 119-132 (E. Robertson, Ed) Springer, New York, N.Y.
Anna Vysochan - Research Specialist
Carrie Kitzmiller - Administrative Coordinator
Nancy Schek - Research Specialist
Tobi Goldberg Maguire - Lab Manager
Yongjun Yu - Research Investigator Senior
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