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Regulation of mTORC1 activity by Tip protein of Herpesvirus saimiri : Herpesvirus saimiri의 Tip 단백에 의한 mTORC1 활성조절 기전 연구

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Authors

김유리

Advisor
조남혁
Major
의과대학 의과학과
Issue Date
2016-08
Publisher
서울대학교 대학원
Keywords
Herpesvirus saimiriTipmTORtransformationmetabolic reprogramming
Description
학위논문 (박사)-- 서울대학교 대학원 : 의과학과, 2016. 8. 조남혁.
Abstract
Herpesvirus saimiri (HVS) is an oncogenic virus that can induce fulminant lymphoma in non-natural primate hosts and transform human T cells in the absence of growth cytokine. Tyrosine kinase interacting protein (Tip) of HVS is a representative oncoprotein, which interacts with multiple cellular proteins such as Lck, STAT3/6, retromer complex, and p80 and is responsible for cellular transformation of T cells. However molecular details how the viral oncogene is involved in the cellular transformation remain elusive. Mammalian target of rapamycin complex 1 (mTORC1), an atypical serine/threonine kinase, has been known as a pivotal regulator of cellular metabolisms and growth. In diverse cancers, regulation of mTORC1 activity in response to environmental nutrients level is often impaired. Here, I report a constitutive activation of mTORC1 in T cells and the molecular mechanisms involved in the regulation of mTORC1 signaling by viral oncogene, HVS Tip. When I assessed the functional activity of mTORC1 by analyzing the phosphorylation of its substrates such as S6K, sustained activation of mTORC1 has been observed in HVS-transformed human T cells as well as T cells or Jurkat cells expressing Tip solely. Interaction of Tip with Lck was required for the upregulation of mTORC1 activity since Lck-binding mutant, TipmLBD failed to enhance mTORC1 activity. The activity of mTORC1 was much less sensitive to glucose deprivation from culture media when T cells expressd Tip. Sustained activation of mTORC1 in the absence of glucose was dependent on the interaction with retromer complex as well as with Lck since T cells expressing Tip mutants which could not interact with the cellular proteins failed to do so. In addition Tip-expressing T cells consumed more oxygen and emitted less acidic metabolites than control cells, suggesting Tip expression might enhance oxidative phosphorylation (OXPHOS) in mitochondria but reduce aerobic glycolysis. Indeed, the level of mitochondrial superoxide was significantly higher in cells expressing Tip, whereas total intracellular ROS level was lower when compared to those of control cells. These metabolic changes by Tip expression were also dependent on the interaction with Lck and retromer complex. I also found that protein level of glucose transporter 1 (GLUT1), which is the primary transporter of glucose in T cells and whose recycling is regulated by retromer complex, was significantly reduced by Tip but not by retromer-binding mutants. It suggests that insensitiveness of mTORC1 to glucose deprivation might be endowed by reduction of GLUT1 level through the impaired function of retromer complex. In summary, HVS Tip upregulated mTORC1 activity in T cells, thereby promoting cellular growth and contributing to T cell transformation. Activation of mTORC1 was dependent on the interaction of Tip with cellular Lck, which also promoted OXPHOS in mitochondria. Furthermore impairment of retromer function via interaction of Tip with VPS35 reduced GLUT1 level and enabled T cells less sensitive to glucose deprivation. The metabolic rewiring of T cells into glucose-independent direction by Tip might contribute to T cell proliferation and malignant transformation.
Language
English
URI
https://hdl.handle.net/10371/122334
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