ROLE OF HUMAN HERPESVIRUS 8 VIRAL INTERLEUKIN-6 SIGNALING IN VIRUS BIOLOGY

HHV-8;primary effusion lymphoma;endoplasmic reticulum;virus replication;STAT3;vIL-6;not listed

Cousins, Emily M.Hayward, S. Diane ;

Johns Hopkins University

关键词: HHV-8;    primary effusion lymphoma;    endoplasmic reticulum;    virus replication;    STAT3;    vIL-6;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/37968/COUSINS-DISSERTATION-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Human herpesvirus 8 (HHV-8) is associated with B cell and endothelial tumors. HHV-8 encodes a viral homolog of interleukin 6 (vIL-6), which promotes the proliferation and survival of virally infected and neighboring cells and induces angiogenesis, suggesting that vIL-6 contributes to HHV-8 malignant pathogenesis. Furthermore, vIL-6 is expressed during viral latency and lytic replication, allowing vIL-6 to function in viral latency maintenance and virus productive replication.Prior to this dissertation research, little was known regarding the role of vIL-6 interactions with its signal transducer (gp130) within the endoplasmic reticulum (ER), where vIL-6 predominantly localizes. High levels of phosphorylated STAT3, a product of vIL-6 signaling, had been observed in HHV-8+ primary effusion lymphomas (PEL), but the mechanism behind STAT3 activation was unclear. The effects of vIL-6 on virus replication were limited to one published study, which failed to detect any influence of vIL-6 in a model culture system. Mechanistically, vIL-6 is distinct from its cellular counterparts because it can signal from the ER, but the biological functions of ER-localized vIL-6/gp130 signaling were unknown. Therefore, the goals of this dissertation were to further characterize ER-localized vIL-6/gp130 interactions, investigate the mechanism(s) responsible for increased STAT3 activation in PEL cells, decipher the roles of gp130-activated STAT and ERK signaling in PEL cell maintenance, and evaluate the role of vIL-6 and the vIL-6/gp130 interaction in HHV-8 replication.Studies performed during this dissertation work demonstrated that ER-localized vIL-6/gp130 signaling in PEL cells contributes to high levels of active STAT3, that vIL-6/gp130 signaling also activates STAT1 and ERK1/2 in PEL cells, that ER-localized vIL-6/gp130 signaling can sustain PEL cell growth and viability, and that STAT3 and ERK1/2 are crucial for cell growth and survival. In addition to promoting the growth and survival of latently infected PEL cells, vIL-6 and gp130 also promote productive virus replication in PEL and endothelial cells. In PEL cells, vIL-6 pro-replication effects require its interaction with gp130 in the ER, where vIL-6/gp130-mediated STAT signaling, and not MAPK signaling, is critical. These studies have expanded our understanding of how vIL-6 functions in normal virus biology and have opened new avenues for targeted HHV-8 therapy.