The murine gammaherpesvirus immediate-early Rta synergizes with IRF4, targeting expression of the viral M1 superantigen to plasma cells.
The murine gammaherpesvirus immediate-early Rta synergizes with IRF4, targeting expression of the viral M1 superantigen to plasma cells.
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鼠伽马鞘病毒立即与IRF4协同作用，靶向病毒M1超抗原对等离子体细胞的表达。
DOI：
10.1371/journal.ppat.1004302
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发表时间：
2014-08
期刊：
影响因子：
6.7
通讯作者：
Speck SH
中科院分区：
文献类型：
--
作者：
O'Flaherty BM;Soni T;Wakeman BS;Speck SH
MHV 68是一种感染实验室小鼠的鼠γ疱疹病毒，因此为表征γ疱疹病毒发病机制的关键方面提供了易于处理的小动物模型。疱疹病毒与其天然宿主一起进化，编码许多基因产物，这些基因产物参与调节宿主免疫应答以促进终身慢性感染的建立和维持。一种这样的蛋白质，MHV 68 M1，是一种分泌蛋白，没有已知的同源物，但已被证明在控制潜伏感染的巨噬细胞的病毒再活化中发挥关键作用。我们之前已经证明，M1驱动Vβ4+ CD8+ T细胞的活化和扩增，Vβ4+ CD8+ T细胞被认为通过分泌干扰素γ参与控制MHV 68再活化。M1表达的作用机制和调控机制尚不清楚。为了深入了解M1的功能，我们着手评估M1基因的表达和转录调控位点。在这里，使用重组病毒表达的荧光蛋白驱动的M1基因启动子，我们确定浆细胞作为主要的细胞类型表达M1在感染的高峰期在脾脏。此外，我们表明，M1基因转录调控的基本病毒立即早期转录激活因子Rta和细胞干扰素调节因子4（IRF4），这两者共同有力地协同驱动M1基因的表达。最后，我们表明，IRF4，浆细胞分化所必需的细胞转录因子，可以直接与Rta相互作用。后一种观察结果提出了Rta和IRF4的相互作用可能参与调节与浆细胞分化相关的MHV 68再活化期间的许多病毒和细胞基因的可能性。通过与宿主的共同进化，γ疱疹病毒获得了有助于感染特定宿主的独特基因。在这里，我们研究MHV 68 M1基因的调控，该基因编码一种调节宿主免疫反应的蛋白质。使用一种策略，使我们能够识别MHV 68感染的细胞在小鼠中，我们已经确定，M1的表达主要限于抗体产生的浆细胞。此外，我们表明，M1基因的表达是由细胞和病毒的因素，这使得病毒微调基因的表达，以响应环境信号。这些发现通过更好地理解M1表达是如何调节的，提供了对M1功能的见解。
MHV68 is a murine gammaherpesvirus that infects laboratory mice and thus provides a tractable small animal model for characterizing critical aspects of gammaherpesvirus pathogenesis. Having evolved with their natural host, herpesviruses encode numerous gene products that are involved in modulating host immune responses to facilitate the establishment and maintenance of lifelong chronic infection. One such protein, MHV68 M1, is a secreted protein that has no known homologs, but has been shown to play a critical role in controlling virus reactivation from latently infected macrophages. We have previous demonstrated that M1 drives the activation and expansion of Vβ4+ CD8+ T cells, which are thought to be involved in controlling MHV68 reactivation through the secretion of interferon gamma. The mechanism of action and regulation of M1 expression are poorly understood. To gain insights into the function of M1, we set out to evaluate the site of expression and transcriptional regulation of the M1 gene. Here, using a recombinant virus expressing a fluorescent protein driven by the M1 gene promoter, we identify plasma cells as the major cell type expressing M1 at the peak of infection in the spleen. In addition, we show that M1 gene transcription is regulated by both the essential viral immediate-early transcriptional activator Rta and cellular interferon regulatory factor 4 (IRF4), which together potently synergize to drive M1 gene expression. Finally, we show that IRF4, a cellular transcription factor essential for plasma cell differentiation, can directly interact with Rta. The latter observation raises the possibility that the interaction of Rta and IRF4 may be involved in regulating a number of viral and cellular genes during MHV68 reactivation linked to plasma cell differentiation. Through coevolution with their hosts, gammaherpesviruses have acquired unique genes that aid in infection of a particular host. Here we study the regulation of the MHV68 M1 gene, which encodes a protein that modulates the host immune response. Using a strategy that allowed us to identify MHV68 infected cells in mice, we have determined that M1 expression is largely limited to the antibody producing plasma cells. In addition, we show that M1 gene expression is regulated by both cellular and viral factors, which allow the virus to fine-tune gene expression in response to environmental signals. These findings provide insights into M1 function through a better understanding of how M1 expression is regulated.
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影响因子：
5.2
作者：
Guito J;Lukac DM
通讯作者：
Lukac DM
影响因子：
6.7
作者：
Collins CM;Speck SH
通讯作者：
Speck SH
影响因子：
5.4
作者：
Laichalk, LL;Thorley-Lawson, DA
通讯作者：
Thorley-Lawson, DA
DOI：
10.1073/pnas.87.10.3743
发表时间：
1990-05-01
影响因子：
11.1
作者：
DRIGGERS, PH;ENNIST, DL;OZATO, K
通讯作者：
OZATO, K
影响因子：
15.3
作者：
Flaño, E;Kim, IJ;Blackman, MA
通讯作者：
Blackman, MA