去泛素化酶USP13调控NLRP3炎症小体活化及机制研究

去泛素化是NLRP3炎症小体活化所必须的过程，但有关NLRP3的去泛素化酶及其作用机制至今认识十分有限。去泛素化酶USP13通过调控多种靶分子的泛素化水平参与多种生理病理过程调节，但尚无证据表明其参与NLRP3活化调控。我们前期研究发现，USP13敲除显著抑制巨噬细胞中NLRP3炎症小体的活化。USP13可结合NLRP3，促进NLRP3去泛素化并增强其蛋白质稳定性。这些结果表明NLRP3可能是USP13的新的靶分子。机制上USP13可通过抑制NLRP3泛素化降解促进NLRP3炎症小体的活化，从而在机体天然免疫调节及NLRP3相关炎症疾病的发生发展中发挥重要作用。本项目拟重点开展以下研究：1）USP13调控NLRP3炎症小体活化2）USP13对小鼠NLRP3炎症小体相关疾病模型的影响3）USP13调控NLRP3炎症小体活化的分子机制4）USP13作为NLRP3炎症小体相关疾病治疗靶点的验证。

Deubiquitination is necessary for NLRP3 inflammasome activation.while the deubiquitinase of NLRP3 and its molecular mechanisms is still unclear. Deubiquitinase USP13 is involved in a variety of physiological and pathological processes through regulation of substrate protein ubiquitination. But there is no evidence to show that USP13 regulates the activation of NLRP3 inflammasome. Our previous studies reveal that USP13 deficiency results in a remarkable attenuation in activation of NLRP3 inflammasome.Moreover, USP13 can bind to NLRP3, which promotes the deubiquitination and stability of NLRP3. These results indicate that NLRP3 may be a novel substrate of USP13. By inhibiting ubiquitin-mediated degradation of NLRP3, USP13 promotes the activation of NLRP3 inflammasome, which plays an important role in regulation of innate immunity and the pathogenesis of NLRP3-associated inflammatory diseases. Therefore, We intend to focus on the following aspects: USP13 regulates the activation of NLRP3 inflammasome; 2) USP13 deficiency suppresses NLRP3-associated inflammatory diseases; 3) Research on regulation of NLRP3 inflammasome activation by USP13; 4) Confirm that USP13 may be a potential target for the treatment of NLRP3-associated inflammatory diseases.