Synergism between IFNß and TNFa: non-canonical functions of STAT2 and IRF9 transcription factors

几乎所有类型的细胞都会分泌细胞因子，这是关键的可溶介质，可以传递危险信号，从而激活适当的生物反应。细胞因子通过细胞表面受体作用，诱导特定的细胞内信息，称为信号级联，最终通过诱导一组特定的基因将信息传递到基因组，以定义适当的反应。解释特定细胞因子如何触发特定分子途径的分子机制是众多研究的焦点。大多数旨在描述细胞因子的信号级联和生物学结果的研究都是在使用单一细胞因子刺激的简化模型中进行的。然而，在生理情况下，细胞不太可能同时受到一种细胞因子的刺激，因为在特定情况下，同时产生多种细胞因子。因此，细胞会对多种细胞因子做出反应，以促进适当的基因表达反应。我们的团队正致力于描述当细胞受到两种细胞因子干扰素和肿瘤坏死因子刺激时发生的信号机制。在病原体检测或炎症条件下，这两种细胞因子水平的升高是显著的。我们正在进行的工作有力地支持了当同时使用干扰素和肿瘤坏死因子时，存在以前未描述的由干扰素和肿瘤坏死因子诱导的信号级联。这些新的信号级联反应与特定的基因表达反应有关。这项研究计划的最终目标是破译细胞以协同方式对干扰素+肿瘤坏死因子做出反应的分子机制。除了提供干扰素+肿瘤坏死因子升高情况的关键细胞生物学理解外，该研究计划还将突出新的范例，这些范例将转化为其他细胞因子组合的刺激。需要生物化学、分子和细胞生物学以及生物信息学分析来解决信号级联的复杂性和动力学问题。我们处于有利的地位，能够长期为这些控制细胞功能的新的基本分子机制的发现做出重大贡献。参加该项目的本科生和研究生将获得生物化学、分子和细胞生物学方面的多样化培训。

Virtually all cell types secrete cytokines, key soluble mediators, to transmit signal of danger to activate an appropriate biological response. Cytokines act via cell surface receptors to elicit specific intracellular messages, known as signaling cascades, which ultimately transfer the message to the genome through the induction of a specific set genes to define an appropriate response. The molecular mechanisms that explain how a specific cytokine triggers a specific molecular pathway are the focus of numerous studies. Most studies aimed at describing the signaling cascades and biological outcome of cytokines are performed in simplified models using single cytokine stimulation. However, in a physiological situation it is highly unlikely that a cell is stimulated by one cytokine at a time as in a particular situation multiple cytokines are produced simultaneously. As a consequence, a cell rather responds to a cocktail of cytokines to foster an appropriate gene expression response. Our group is working to describe the signaling mechanisms that occurs when cells are stimulated with two cytokines, Interferon and TNF. Elevated levels of both cytokines are notably induced upon pathogen detection or in inflammatory conditions. Our work in progress strongly supports the existence of previously uncharacterized signaling cascades induced by the Interferon and TNF when used simultaneously. These novel signaling cascades are associated with the specific gene expression responses. The ultimate goal of this research program is to decipher the molecular mechanisms by which cells specifically respond in a coordinated fashion to IFN+TNF. In addition to providing key cell biology understanding of situations with elevated IFN+TNF, this research program will highlight novel paradigms that will translate to stimulation by other combination of cytokines. Biochemistry, molecular and cellular biology and bioinformatics analyses are required to solve the complexity and dynamics of the signaling cascades. We are in a privileged position to contribute significantly on a long-term basis to the discovery of these novel basics molecular mechanisms that control cell function. Undergraduate and graduate students participating to this program will gain a diversified training in biochemistry and molecular and cellular biology.