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

先天免疫通过与模式识别受体的相互作用识别保守的微生物结构。其中，Toll样受体（TLR）已被确定为在先天防御机制的激活中发挥关键作用。虽然现在对TLR刺激后导致细胞活化的信号转导过程有了广泛的了解，但对随后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因子（SOCS）蛋白已被鉴定为JAK/STAT依赖性细胞因子受体信号传导的可诱导反馈抑制剂。此外，我们和其他人已经表明，SOCS分子在先天免疫系统的细胞中也起着重要的调节作用。为此，SOCS蛋白现已显示也调节TLR信号传导的部分方面。然而，SOCS在先天免疫中的确切分子机制尚未确定。此外，最近的工作表明，SOCS可能会采取行动，在迄今为止意想不到的模式，涉及蛋白修饰泛素和蛋白酶体降解。该项目的主要目标是：（1）分析SOCS蛋白的分子作用模式，（2）检查TLR触发后自分泌I型IFN信号传导的作用，以及（3）分析SOCS作为细胞内微生物感染调节剂的作用。

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.