HSPA13对于TNF-α下游响应信号通路方向选择的调控

Tumor Necrosis Factor α (TNFα) is a multi-functional cytokine that can induce transcription activation to inhibit apoptosis, promote cell survival, induce inflammation, or can induce apoptosis or necroptosis. Therefore, TNFα pathway is crucial in many physiological processes, including immunity, cell & tissue growth, cell survival, tumor development, etc. Due to its roles in promoting inflammation and inhibiting tumor growth, TNFα is a hot target for anti-cancer or anti-autoimmune diseases. However, the clinical application of TNFα-related drugs is limited due to the fact that TNFα pathway can induce multiple signalings with huge difference and even opposite effects. Thus, the elucidation of the mechanism bifurcating different signaling pathways downstream of TNFα would be of great importance in promoting clinical use of TNFα-related drugs. This project aims to solve this critical question: the mechanism switching the outcome of TNFα signaling between pro-growth/inflammation and pro-apoptotic. Our preliminary studies showed that a protein HSPA13 is key to this process. Loss of HSPA13 switches TNFα pathway from pro-growth to pro-apoptotic. This project aims to further investigate on the role of this protein in TNFα signaling and to elucidate the molecular mechanism of HSPA13‘s regulation on the TNFα pathway.

肿瘤坏死因子α（TNFα）是一种多效细胞因子，可以介导细胞转录激活从而抑制凋亡、促进炎症发生，亦可以致使细胞发生程序性死亡，在机体免疫防御、组织再生与延展、癌症发生与转移等多种生理和病理过程中都发挥至关重要的作用。由于TNFα在炎症发生及抑制肿瘤方面的作用，其在肿瘤防治和抗自免疫疾病方面都是很好的靶点。然而TNFα下游有着细胞增殖，炎症发生，细胞凋亡，程序性坏死等差异很大且矛盾的多种信号通路，因此对于其信号通路之间的分流调控的研究不完整是限制了其临床应用的重要原因。本项目立足于解决TNFα信号通路研究中的关键问题，即其下游促生长/炎症与促凋亡的信号通路之间的分流的机制。前期工作已筛选到一个调控TNFα下游信号通路分流的关键蛋白HSPA13，该蛋白的缺失导致TNFα下游的通路从促生长转为促凋亡。本项目将进一步阐明HSPA13调控TNFα下游信号通路的具体分子机制。