染色质调控蛋白PTIP促进B细胞发育和功能的分子机制研究

B cell receptor (BCR) signaling and downstream NF-κB activity are crucial for the development and functionality of all major B cell subsets, yet the molecular regulators and mechanism in these signaling events are not fully understood. PTIP (Pax transactivation domain-interacting protein) chromatin regulator, it has been described as an adaptor protein and is implicated in gene regulation, DNA repair. It is required for sterile transcription of switch regions at the Ig heavy-chain (Igh) locus and subsequent IgH CSR (class switch recombination) to multiple IgG isotypes. In our recent paper, We found that PTIP as a licensing factor for humoral immunity that acts at several junctures of B lineage maturation, effector cell differentiation and functionally activity through regulating the NF-κB pathway. It is essential to establish steady-state and post-immune antibody production in vivo. PTIP-deficient mice exhibit Hypogammaglobulinemia, the defects in B-cell development and in NF-κB activity, that are similar to human primary common variability immunodeficiency (CVID). PTIP contains six BRCT domains, but the role of each domain in promoting humoral immunity is unclear. In this proposal, we will aim to study (1) the roles of PTIP 6 BRCT domains in promoting B cell development, functionality; (2) whether BRCT domain associates with other protein to form the complex in regulating B cell development and founctionality. Decode the regulatory mechanism of PTIP 6 BRCT domains on cellular signaling will generate valuable new insight for human B cell and relative disease.

B细胞受体(BCR)信号系统及下游的NF-κB活性对B细胞的发育和功能至关重要，但分子水平的调控者及其作用机理并不完全清楚。染色质调控蛋白PTIP，除参与基因调控、DNA修补、促进IgH转录和类别转换重组外，我们最近发表的论文首次发现PTIP是体液免疫中重要的调控因子，其通过调控NF-κB活性来促进B细胞发育和功能，及建立天然抗体稳态和免疫后特异抗体的产生。缺陷鼠表现出严重的低IgG血症、B细胞发育障碍和NF-κB缺陷，与人类常见变异性免疫缺陷症非常相似。PTIP包含6个BRCT结构，但每个结构在促进体液免疫中的作用却不清楚。本课题中，我们将解码PTIP 6个BRCT结构：(1)在促进B细胞亚群的发育,活化和功能中的各自作用，(2)对B细胞的调控作用是否需要关联其它特异性蛋白，形成功能性复合物。解码PTIP在细胞信号传导上的调控机理，将为人类B细胞和相关疾病的研究提供有价值的新见解。