泛素E3连接酶Trim35靶向RelB降解在弥漫大B细胞淋巴瘤中的机制研究

非经典NF-κB通路在弥漫大B细胞淋巴瘤（DLBCL）发生中具有重要作用，并通过促进抗凋亡靶基因的表达导致DLBCL对化疗不敏感。在细胞浆内NIK和IKKα介导p100加工为p52被认为是非经典NF-κB通路的主要调控方式。然而，非经典NF-κB通路在核内的调控机制目前尚不清楚。我们的结果显示在DLBCL中E3连接酶Trim35低表达，Trim35抑制DLBCL细胞增殖。Trim35和RelB结合并促进RelB发生泛素化和降解，此外当非经典NF-κB通路激活时会促进RelB的泛素化。据此我们推测：E3连接酶Trim35通过靶向RelB在核内负调控NF-κB非经典通路从而影响DLBCL的发生发展与治疗。本课题将探讨Trim35靶向RelB降解调控非经典NF-κB通路和DLBCL的机制，我们还将评估在Trim35低表达的DLBCL细胞中靶向非经典NF-κB通路对于化疗疗效的影响。

The non-canonical NF-κB pathway plays a critical role in the development of diffuse large B-cell lymphoma (DLBCL),in addition, this pathway also reduces the sensitivity of DLBCL cells to chemotherapy via inducing anti-apoptotic gene expression. In cytosol, NIK and IKKα-meidiated p100 processing to p52 is believed to be the main regulatory mechanism for this pathway. However, how the non-canonical NF-κB pathway is modulated in nuclear is poorly understood. Our preliminary studies indicated that E3 ligase Trim35 was downexpressed in DLBCL tissues. Overexpreesion of Trim35 in DLBCL cells inhibited cell proliferation. Through a proteomic approach to screen Trim35-interacting proteins, we found that Trim35 interacted with RelB and promoted the ubiquitination of RelB. Furthermore, overexpression of Trim35 accelerated the degradation of RelB through proteasome pathway.In addition,we found the activation of the non-canonical NF-κB pathway also induced the ubiquitination of RelB. According to these data, we hypothesize that Trim35 regulates the non-canonical NF-κB pathway through targeting RelB for degradation in nuclear, which in turn affects the development and treatment of DLBCL. To test this hypothesis, cultured cancer cells, mouse model and the histological analysis of cancer tissue sections will be applied to investigate the role of Trim35 in the non-canonical NF-κB pathway and the development of DLBCL through targeting RelB for degradation, as well as its involvement in the chemotherapy.