Ubiquitylation and the Regulation of Immune Homeostasis

描述（由申请人提供）：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。TLR信号的适当调节不仅限制了炎症反应的强度和持续时间，而且还可能维持肠道内的免疫稳态，在肠道中，大量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，在体内需要终止TLR诱导的髓细胞信号和防止过度的炎症反应。我们的初步数据表明A20对体内限制TLR信号至关重要。此外，我们的研究结果表明，A20可能是一种通过直接调节TLR信号蛋白（如TRAF6）的泛素化状态来执行这一关键功能的新型酶。

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.