Intrinsic p53 activation restricts gammaherpesvirus driven germinal center B cell expansion during latency establishment

IF 14.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Shana M. Owens, Jeffrey M. Sifford, Gang Li, Steven J. Murdock, Eduardo Salinas, Darby Oldenburg, Debopam Ghosh, Jason S. Stumhofer, Intawat Nookaew, Mark Manzano, J. Craig Forrest
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Abstract

Gammaherpesviruses are DNA tumor viruses that establish lifelong latent infections in lymphocytes. For viruses such as Epstein-Barr virus and murine gammaherpesvirus 68, this is accomplished through a viral gene-expression program that promotes cellular proliferation and differentiation, especially of germinal center B cells. Intrinsic host mechanisms that control virus-driven cellular expansion are incompletely defined. Using a small-animal model of gammaherpesvirus pathogenesis, we demonstrate in vivo that the tumor suppressor p53 is activated specifically in B cells latently infected by murine gammaherpesvirus 68. In the absence of p53, the early expansion of murine gammaherpesvirus 68 latency greatly increases, especially in germinal center B cells, a cell type whose proliferation is conversely restricted by p53. We identify the B cell-specific latency gene M2, a viral promoter of germinal center B cell differentiation, as a viral protein sufficient to elicit a p53-dependent anti-proliferative response caused by Src-family kinase activation. We further demonstrate that Epstein-Barr virus-encoded latent membrane protein 1 similarly triggers a p53 response in primary B cells. Our data highlight a model in which gammaherpesvirus latency gene-expression programs that promote B cell proliferation and differentiation to facilitate viral colonization of the host trigger aberrant cellular proliferation that is controlled by p53.

Abstract Image

内在的p53激活限制了γ疱疹病毒驱动的生发中心B细胞在潜伏期建立期间的扩增
γ疱疹病毒是在淋巴细胞中建立终身潜伏感染的DNA肿瘤病毒。对于像eb病毒和小鼠γ疱疹病毒68这样的病毒,这是通过促进细胞增殖和分化的病毒基因表达程序来完成的,尤其是生发中心B细胞。控制病毒驱动的细胞扩张的内在宿主机制尚未完全确定。利用伽玛疱疹病毒发病机制的小动物模型,我们在体内证明肿瘤抑制因子p53在潜伏感染小鼠伽玛疱疹病毒68的B细胞中特异性激活。在缺乏p53的情况下,小鼠γ疱疹病毒68潜伏期的早期扩张大大增加,特别是在生发中心B细胞中,这种细胞类型的增殖反过来受到p53的限制。我们发现B细胞特异性潜伏期基因M2是生发中心B细胞分化的病毒启动子,作为一种病毒蛋白,足以引发由src家族激酶激活引起的p53依赖性抗增殖反应。我们进一步证明,eb病毒编码的潜伏膜蛋白1在原代B细胞中类似地触发p53反应。我们的数据强调了一个模型,在这个模型中,伽马疱疹病毒潜伏期基因表达程序促进B细胞增殖和分化,从而促进病毒在宿主的定植,从而触发由p53控制的异常细胞增殖。
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来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
期刊介绍: Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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