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标题: 上海巴斯德所揭示死亡信号在疱疹病毒相关淋巴瘤中新功能 [打印本页]

作者: ipsvirus    时间: 2016-10-20 17:08
标题: 上海巴斯德所揭示死亡信号在疱疹病毒相关淋巴瘤中新功能
在正常情况下,当细胞表面死亡受体CD95与配体CD95L结合被激活时,就会触发细胞凋亡机制。然而近年来研究发现CD95/CD95L还可促发细胞的活化和增殖,而不是细胞死亡,其表达异常与肿瘤以及某些自身免疫性疾病的发生、发展有着密切联系。近日,来自中科院上海巴斯德研究所梁小珍研究员课题组发现了CD95非凋亡信号能够抑制抗凋亡的淋巴瘤细胞中疱疹病毒的复制,相关研究成果发表在新一期的《病毒学杂志》(Journalof Virology)上。

疱疹病毒(Herpesviruses)是一类具有包膜的DNA病毒,可分为αβγ等亚科。疱疹病毒在自然界中广泛存在,引起人和许多动物的感染,主要侵犯外胚层来源的组织,包括皮肤、粘膜和神经组织。感染部位和引起的疾病多种多样,并有潜伏感染的趋向,严重威胁人类健康。α疱疹病毒(如HSV)增殖速度快,引起细胞病变。β疱疹病毒(如CMV),生长周期长,感染细胞形成巨细胞。γ疱疹病毒(包括EBVKSHVMHV68),感染的靶细胞是淋巴样细胞,可在B淋巴细胞中建立潜伏感染,引起细胞增生及淋巴瘤。

CD95,又称FasApo-1,是细胞膜表面受体TNF/NGF-R家族的成员。免疫细胞表面表达的高水平CD95L与靶细胞表面的CD95相互识别,通过CD95触发靶细胞内部的凋亡程序,CD95胞内的死亡区募集连接程序分子FADD,FADD招募Caspase8,形成凋亡诱导信号复合物(Death-inducingsigna1ing complexDISC)最终引起Caspase3活化导致凋亡。过去科学家一直认为,失去死亡受体可能是肿瘤形成的一个先决条件。然而,后面发现在许多癌细胞中其CD95的浓度一直很高,在癌细胞快速生长和繁殖时也是如此,而且诱导CD95实际上会促进癌细胞的生长。因而CD95/CD95L非凋亡信号通路受到极大关注。CD95/CD95L的非凋亡活性可通过NF-κB通路,MAPK通路(ERK1/2p38JNK1/2)PI3K通路介导,刺激细胞存活和增殖,促进趋化因子产生和炎症反应,甚至调节细胞的迁移和侵袭。



B 细胞淋巴瘤在年长和有免疫缺陷的人群中比较普遍,与γ疱疹病毒感染紧密相关。但是,在γ疱疹病毒感染条件下,B 细胞淋巴瘤的产生和发展机制目前研究的还不是很清楚。在本研究中,硕士研究生谭令兵等在梁小珍研究员指导下分析了CD95/CD95L这一信号通路对疱疹病毒相关的B细胞淋巴瘤的效应作用。研究发现,当激活EBVMHV68疱疹病毒相关淋巴瘤细胞的CD95受体时,绝大部分细胞都会发生凋亡,但是会有一小部分细胞能够抵抗凋亡而存活下来,并表现出略微更快的增殖速度。后续研究发现这部分抗凋亡淋巴瘤细胞表面的CD95因活化而内吞导致细胞表面CD95量下调而存活,并且这种量下调是可逆的,当去除CD95激活剂后,其在表面的表达量就会恢复。


激活B淋巴细胞的BCR信号可以介导疱疹病毒由潜伏感染进入裂解复制周期,研究人员发现在BCR信号活化后,再激活CD95信号通路能够明显抑制EBVMHV68裂解周期蛋白的表达,说明CD95信号活化可以抑制抗凋亡B淋巴细胞中的疱疹病毒的复制。机制研究发现,这一抑制作用并不依赖与BCR信号通路,而是CD95非凋亡信号通路介导IFN-β产生而发挥的抗病毒作用。



该研究揭示了CD95死亡受体的非凋亡信号通路在γ疱疹病毒相关的抗凋亡的B细胞淋巴瘤中抑制病毒复制的功能及其机制,有助于人们对理解γ疱疹病毒感染如何调控B 细胞淋巴瘤的产生和发展。研究得到国家科技部和国家自然科学基金等项目资助。


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作者: ipsvirus    时间: 2016-10-20 17:09
CD95 Signaling Inhibits B Cell Receptor-Mediated Gammaherpesvirus Replication in Apoptosis-Resistant B Lymphoma Cells

Lingbing Tan, Chaocan Zhang, Julien Dematos, Linlin Kuang, Jae U. Jung and Xiaozhen Liang

ABSTRACT
While CD95 is an apoptosis-inducing receptor and has emerged as a potential anticancer therapy target, mounting evidence shows that CD95 is also emerging as a tumor promoter by activating nonapoptotic signaling pathways. Gammaherpesviral infection is closely associated with lymphoproliferative diseases, including B cell lymphomas. The nonapoptotic function of CD95 in gammaherpesvirus-associated lymphomas is largely unknown. Here, we show that stimulation of CD95 agonist antibody drives the majority of sensitive gammaherpesvirus-transformed B cells to undergo caspase-dependent apoptosis and promotes the survival and proliferation of a subpopulation of apoptosis-resistant B cells. Surprisingly, CD95-mediated nonapoptotic signaling induced beta interferon (IFN-β) expression and correlatively inhibited B cell receptor (BCR)-mediated gammaherpesviral replication in the apoptosis-resistant lymphoma cells without influencing BCR signaling. Further analysis showed that IFN-β alone or synergizing with CD95 blocked the activation of lytic switch proteins and the gene expression of gammaherpesviruses. Our findings indicate that, independent of its apoptotic activity, CD95 signaling activity plays an important role in blocking viral replication in apoptosis-resistant, gammaherpesvirus-associated B lymphoma cells, suggesting a novel mechanism that indicates how host CD95 prototype death receptor controls the life cycle of gammaherpesviruses independent of its apoptotic activity.

IMPORTANCE
Gammaherpesviruses are closely associated with lymphoid malignancies and other cancers. Viral replication and persistence strategies leading to cancer involve the activation of antiapoptotic and proliferation programs, as well as evasion of the host immune response. Here, we provide evidence that the stimulation of CD95 agonist antibody, mimicking one of the major mechanisms of cytotoxic T cell killing, inhibits B cell receptor-mediated gammaherpesviral replication in CD95 apoptosis-resistant lymphoma cells. CD95-induced type I interferon (IFN-β) contributes to the inhibition of gammaherpesviral replication. This finding sheds new light on the CD95 nonapoptotic function and provides a novel mechanism for gammaherpesviruses that helps them to escape host immune surveillance.

http://jvi.asm.org/content/90/21/9782.full
作者: wwwkkk83    时间: 2016-10-21 07:30





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