学位论文详细信息
RNA virus modulation of IFN, PI3K and apoptosis
Apoptosis;RNA viruses;Interferon--Antagonists
Killip, Marian J. ; Randall, R. E. ; Randall, R. E.
University:University of St Andrews
Department:Biology (School of)
关键词: Apoptosis;    RNA viruses;    Interferon--Antagonists;   
Others  :  https://research-repository.st-andrews.ac.uk/bitstream/handle/10023/777/Marian%20J.%20Killip%20PhD%20Thesis.pdf?sequence=7&isAllowed=y
来源: DR-NTU
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【 摘 要 】

Interferon (IFN) and phosphatidylinositol 3-kinase (PI3K) are apoptosis regulatorsthat are targeted by viruses to promote survival of infected cells. Significant crosstalkexists between IFN and PI3K, and this study sought to investigate the relationshipsbetween IFN, PI3K and apoptosis during virus infection. Parainfluenza virus 5 (PIV5)and influenza A virus (IAV) are both negative-sense single-stranded RNA virusesthat encode multifunctional proteins in order to maximise their genome codingcapacity. The PIV5 V and IAV NS1 proteins are well-studied as IFN antagonists and,in addition, both are reported to modulate PI3K signalling. Less well-studied is therole of these proteins in apoptosis regulation; the ability of V and NS1 to inhibitapoptosis was therefore investigated. PIV5/V was found to limit cell death inresponse to a number of apoptosis inducers in a manner that required its STAT1-degradative activity and also inhibited activation of the PI3K downstream target, Akt.IAV/NS1 binds directly to PI3K to stimulate its activity, and this is reported to mediateanti-apoptotic signalling during IAV infection. However, a virus expressing an NS1unable to bind PI3K did not induce more apoptosis than wt virus. NS1 expression,either in a stable cell-line or during virus infection, was also unable to protect cellsfrom pro-apoptotic stimuli. NS1-mediated PI3K activation similarly had no effect onIFN production or ISG expression in infected cells. In contrast, other NS1 mutantviruses induced large amounts of apoptosis. These viruses also induced significantlevels of IFN and were unable to cause apoptosis in IFN-deficient cells, indicatingthat NS1 limits apoptosis induction through its IFN antagonist functions. Theimplications of this work for anti-cancer and anti-viral therapies are discussed.

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