Regulation of innate immune responses by suppressor of cytokine signaling (SOCS) proteins

通过细胞因子信号传导 (SOCS) 蛋白抑制因子调节先天免疫反应

• 批准号: 19207112
• 负责人: Professor Dr. Alexander Dalpke
• 金额: --
• 依托单位: Abteilung Medizinische Mikrobiologie und Hygiene
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/19207112?language=en
• 关键词: Regulation; innate; immune; responses; suppressor

Innate immunity recognizes conserved microbial structures through their interaction with pattern recognition receptors. Among these, Toll-like receptors (TLR) have been identified to play a crucial role for the activation of innate defense mechanisms. While there is now extensive knowledge as to the signal transduction processes leading to cellular activation upon TLR stimulation, still little is known about subsequent regulatory circuits especially negative-regulation. Shutting down initial TLR activation is absolutely required to limit the potentially detrimental effects of inflammation. Suppressor of cytokine signaling (SOCS) proteins have been identified as inducible feedback inhibitors for JAK/STAT dependent cytokine receptor signaling. Moreover, we and others have shown that SOCS molecules also play an important regulatory role in cells of the innate immune system. To this, SOCS proteins have now been shown also to modulate partial aspects of TLR signaling. However, the precise molecular mechanisms of SOCS in innate immunity are yet to be identified. Moreover, recent work suggests that SOCS might act in a so far unanticipated mode involving the protein modifier ubiquitin and proteasomal degradation. Central goals of this project are: (1) to analyze the molecular modes of action of SOCS proteins, (2) to examine the role of autocrine type I IFN signaling upon TLR triggering and (3) to analyze the role of SOCS as a regulator of infections with intracellular microbes.

先天免疫通过与模式识别受体的相互作用来识别保守的微生物结构。其中，Toll 样受体 (TLR) 已被确定在激活先天防御机制中发挥着至关重要的作用。虽然现在对 TLR 刺激导致细胞激活的信号转导过程有了广泛的了解，但对后续的调节回路尤其是负调节仍然知之甚少。为了限制炎症的潜在有害影响，绝对需要关闭初始 TLR 激活。 细胞因子信号传导抑制剂 (SOCS) 蛋白已被确定为 JAK/STAT 依赖性细胞因子受体信号传导的诱导反馈抑制剂。此外，我们和其他人已经证明 SOCS 分子在先天免疫系统的细胞中也发挥着重要的调节作用。为此，SOCS 蛋白现已被证明可以调节 TLR 信号传导的部分方面。然而，SOCS 在先天免疫中的精确分子机制尚未确定。此外，最近的研究表明，SOCS 可能以迄今为止未预料到的方式发挥作用，涉及蛋白质修饰剂泛素和蛋白酶体降解。该项目的中心目标是：(1) 分析 SOCS 蛋白的分子作用模式，(2) 检查自分泌 I 型 IFN 信号传导对 TLR 触发的作用，(3) 分析 SOCS 作为细胞内微生物感染调节剂的作用。