治病菌感染肺组织后引起的失控的“细胞因子风暴” ,从而导致急性肺损伤(ALI)。Single immunoglobulin interleukin-1-related receptor (Sigirr)是IL-37的受体,具有显著的抑制细胞因子风暴的作用。然而，Sigirr的蛋白调节机理还没有任何报道。本项目前期研究发现Sigirr蛋白的稳定性是由位点特异性泛素化修饰所调节的。 去泛素化酶(USP13)能够去除Sigirr的泛素链修饰，从而增加Sigirr的稳定性及其抗炎作用。我们推测USP13对Sigirr稳定性的调节在肺组织自身抗炎反应和减轻肺炎导致的ALI的过程中具有重要的病理学意义。本课题将运用细胞和动物模型阐明(1) Sigirr泛素化对炎症反应的作用；(2)USP13稳定Sigirr的分子机制; (3)增强 USP13的表达对减轻炎症反应和ALI程度的作用。

An unresolved systemic cytokine storm caused by bacterial infection is a hallmark of acute lung injury (ALI). The robust acute inflammatory response, through Toll Like Receptors (TLRs) and interleukin-1R like receptors (ILRs), trigger detrimental effects including severe tissue injury. ALI remains high mortality. Hence, an unmet scientific need is to understand the molecular regulation of anti-inflammatory responses that diminish the severity of ALI. Single immunoglobulin interleukin-1-related receptor (Sigirr), which is also known as Toll/IL-1 receptor 8, exhibits an anti-inflammatory effect against TLRs and ILRs signaling. Sigirr has been found as IL-37 receptor. Both IL-37 and Sigirr have been recognized as major therapeutic targets to lessen cytokine storm, however, very little is known regarding the molecular regulation of Sigirr stability. In our preliminary data, we discovered that Sigirr is site specific poly-ubiquitinated and the ubiquitination regulates Sigirr internalization and degradation in the proteasome. Its levels were reduced in response to pro-inflammatory stimulation. Ubiquitin-specific protease 13 (USP13) deubiquitinates Sigirr, thereby enhancing Sigirr stability and anti-inflammatory effects. We hypothesize that regulation of Sigirr stability by USP13 may play a critical role in the pathogenesis of ALI. The proposal will use our expertise in molecular and cell biology and pre-clinical murine models to investigate (1) the effect of Sigirr ubiquitination on inflammatory responses; (2) molecular regulation of Sigirr stability by USP13; and (3) the effect of USP13 on reduction of inflammatory responses and severity of ALI. The application will provide new potential therapeutic targets for treating ALI.