AMPK介导的RIPK1磷酸化在能量压力引起的细胞死亡中的作用与机制研究

AMPK是能量压力的重要感应器，除了调控能量代谢，使细胞恢复能量稳态，还具有抑制细胞死亡的重要功能。已知AMPK缺失的细胞对能量压力诱导的细胞死亡更加敏感，AMPK敲除的小鼠胚胎致死，相关分子机制均不清楚。我们前期研究发现，能量压力致死依赖于细胞死亡调控核心蛋白RIPK1的激酶活性；能量压力可以促进RIPK1-S416位磷酸化；RIPK1-S416位磷酸化依赖于AMPK；RIPK1-S416A突变的细胞对能量压力致死更加敏感。据此我们假设：在能量压力下AMPK被激活，一方面调控能量代谢，使细胞恢复能量稳态，另一方面通过磷酸化RIPK1抑制RIPK1活化和细胞死亡，使细胞有足够时间恢复能量稳态。在生理情况下，AMPK介导的RIPK1磷酸化维持了胚胎的正常发育，AMPK-RIPK1轴具有对胚胎发育的质量控制作用。该项目将为研发针对AMPK和细胞死亡相关的疾病药物提供新的理论基础和靶向策略。

AMPK is an important sensor of energy stress, which can regulate energy metabolism as well as inhibit cell death. It’s unclear why AMPK-deficient cells are more sensitive to energy stress-induced cell death, and AMPK-knockout mice are embryonic lethal at E10.5. We found that energy stress-induced cell death depends on the kinase activity of RIPK1, a master regulator of cell death; energy stress promotes RIPK1-S416 phosphorylation; RIPK1-S416 phosphorylation depends on AMPK activation; RIPK1-S416A mutant cells are more sensitive to energy stress-induced cell death. We hypothesized that, AMPK, when activated under energy stress, on the one hand, regulates energy metabolism to restore energy homeostasis as soon as possible, and on the other hand, phosphorylates RIPK1 to inhibit its activation and cell death, thus making the cells have sufficient time to restore energy homeostasis. In physiological conditions, AMPK-mediated RIPK1 phosphorylation may play a role in the quality control of embryo development. The project will provide new theoretical insights and targeting strategies for the development of drugs targeting human diseases related to AMPK and cell death.