Ubiquitylation and the Regulation of Immune Homeostasis

描述(申请人提供)：真核细胞上的Toll样受体(TLRs)介导微生物分子的识别，并调节宿主对微生物病原体的反应。对TLR信号的适当调节不仅可以限制炎症反应的强度和持续时间，还可以维持肠道的免疫稳态，因为肠道中有大量的微生物病原体与宿主细胞共存。我们实验室最近的研究表明，A20是一种新的蛋白质，它是终止TLR诱导的髓系细胞信号和防止体内过度炎症反应所必需的。我们的初步数据表明，A20在体内对限制TLR信号是必不可少的。此外，我们的发现表明，A20可能是一种新的酶，通过直接调节TLR信号蛋白如TRAF6的泛素化状态来执行这一关键功能。 这些修饰可能导致TLR信号蛋白的失活和降解。这些令人兴奋的初步发现为我们提供了独特的机会来检验我们的中心假设，即A20调节信号蛋白的泛素化、TLR信号和免疫稳态。这项应用代表了MA实验室的遗传和细胞专家与Pickart实验室的生化专业知识之间的协同工作，以确定：(I)A20是否对于调节小鼠的TLR反应是必不可少的；(Ii)A20是否调节关键TLR信号蛋白的泛素化；以及(Iii)A20如何识别泛素化的蛋白质并可能同时作为去泛素化酶和E3发挥作用。这些研究的结果有望对A20如何将泛素化调节与疾病联系起来提供重要的见解。

DESCRIPTION (provided by applicant): Toll like receptors (TLRs) on eukaryotic cells mediate the recognition of microbial molecules and regulate host responses to microbial pathogens. Proper regulation of TLR signals not only restricts the intensity and duration of inflammatory responses, but may also maintain immune homeostasis in the intestine, where a plethora of microbial pathogens co-exist with host cells. Recent studies from our labs indicate that A20 is a novel protein that is required for terminating TLR induced signals on myeloid cells and for preventing excessive inflammatory responses in vivo. Our preliminary data suggest that A20 is essential for restricting TLR signals in vivo. Moreover, our findings suggest that A20 may be a novel enzyme that performs this critical function by directly modulating the ubiquitylation status of TLR signaling proteins such as TRAF6. These modifications may cause both de-activation and degradation of TLR signaling proteins. These exciting preliminary findings provide us with unique opportunities to test our central hypothesis that A20 regulates ubiquitylation of signaling proteins, TLR signals, and immune homeostasis. This application represents a synergistic effort between the genetic and cellular expertises of the Ma lab and the biochemical expertise of the Pickart lab to determine: (i) whether A20 is essential for regulating TLR responses in mice; (ii) whether A20 regulates ubiquitylation of critical TLR signaling proteins; and (iii) how A20 recognizes ubiquitylated proteins and may function as both a de-ubiquitylating enzyme and an E3. Results from these studies promise to yield significant insights into how A20 links the regulation of ubiquitylation with disease.