Role of ubiquitin networks in NF-κB driven B cell neoplasms (P06)

NF-κB的活化受依赖于蛋白磷酸化和泛素系统活性的信号级联调节。我们鉴定了泛素连接酶KBTBD 7、KLHL 21和FBXO 41作为ABC型DLBCL中介导NF-κB活化的候选物，并发现BCMA，一种NF-κB活化剂和多发性骨髓瘤（MM）细胞免疫治疗的靶点，受泛素蛋白酶体系统（UPS）调节。该项目将努力获得关于泛素连接酶如何维持DLBCL中NF-κB活性的整体机制理解，UPS如何指导MM中BCMA活性和表达，以及这些见解如何提出新的可操作的治疗靶点。

Activation of NF-κB is regulated by signalling cascades that depend on protein phosphorylation and activities of the ubiquitin system. We identified the ubiquitin ligases KBTBD7, KLHL21 and FBXO41 as candidates that mediate NF-κB activation in ABC-type DLBCL and found BCMA, an NF-κB activator and target for cellular immunotherapies in multiple myeloma (MM), to be regulated by the ubiquitin proteasome system (UPS). This project will strive to obtain a holistic mechanistic understanding of how ubiquitin ligases sustain NF-κB activity in DLBCL, how the UPS can direct BCMA activity and expression in MM and how these insights can forward novel actionable therapeutic targets.