Bclaf1在TNF-α信号通路中的作用与机制

Tumor necrosis factor (TNF-α) is an important proinflammatory cytokine implicated in multiple inflammation-related diseases and cancer. TNF-α stimulation induces cells to up-regulate and secrete proinflammatory cytokines, and also apoptosis and necroptosis under certain conditions. TNF-α induced cell death is normally suppressed by its induced inflammatory branch of signaling pathway. However, the underlying mechanism is not well understood. In our previous study, we found that the transcription regulatory protein Bclaf1 plays a critical role in the chronic DNA damage induced proinflammatory cytokine secretion. We further found that knockdown or knockout of Bclaf1 in cells renders the cells more susceptible to the TNF-α induced apoptosis. Based on these observations, we propose that Bclaf1 may be a novel player in TNF-α signaling, and inhibit apoptosis by facilitating the TNF-α induced transcriptional upregulation of anti-apoptotic molecules. In this proposal, we plan to determine the role of Bclaf1 in TNF-α signaling, decipher the mechanism by which Bclaf1 inhibits apoptosis and explore how Bclaf1 responds to TNF-α stimulation. We expect the study coming from this proposal will help understand the regulation of TNF-α signaling and the functions of Bclaf1 in inflammatory.

肿瘤坏死因子（TNF-α）是重要的炎性细胞因子，与肿瘤等多种疾病相关。TNF-α既可刺激细胞产生炎性因子，又可诱导细胞凋亡和坏死，且后者受到前者的多重抑制，但具体机制还不完全清楚。我们前期工作显示转录调控因子Bclaf1在慢性DNA损伤诱导的炎性反应中起重要作用（Cell Death&Differentiation，2016）。下调Bclaf1后，TNF-α诱导的细胞凋亡显著提高。我们推测Bclaf1可能是TNF-α信号通路中的一个重要分子，通过转录调控相关基因抑制细胞凋亡。本课题我们将围绕此中心假设，系统研究Bclaf1在TNF-α信号通路中的作用；从转录调控和信号转导角度解析Bclaf1抑制TNF-α诱导细胞凋亡的机制，并探究Bclaf1在TNF-α信号通路中的应答机制。这些研究将极大提高对Bclaf1炎性功能及TNF-α通路调控机制的认识，为揭示Bclaf1与炎性疾病的关系奠定基础。

肿瘤坏死因子（TNF）在维持组织器官稳态和炎症反应中扮演着重要角色。TNF信号通路非常复杂且受到多层次的精细调控，其失调则可能导致类风湿性关节炎等多种疾病。本研究首次揭示了多功能蛋白Bclaf1在TNF诱导的细胞凋亡通路中的重要调控作用，并阐明了其具体作用机制。项目研究结果表明，在多种细胞系中，Bclaf1缺失或下调显著增强了TNF诱导的细胞凋亡。研究还发现，Bclaf1不参与TNF诱导的上游信号通路，如NF-κB的活化和入核，但在细胞核中可以与NF-κB成员p50相互结合，并协同作用来转录上调抗凋亡蛋白c-FLIP。进一步研究表明，Bclaf1通过上调c-FLIP的表达量，从而在TNF诱导的凋亡复合体中抑制caspase 8的活化，进而抑制细胞凋亡。在小鼠模型中，敲低Bclaf1的表达显著增强了TNF诱导的小肠损伤和细胞凋亡。这些研究结果表明，Bclaf1是调控细胞对TNF敏感性的重要蛋白，为深入研究Bclaf1在TNF相关疾病中的功能提供了理论基础。该研究加深了对TNF信号通路及其调控机制的认识，具有重要的生理和病理意义。