Yao Zhenyu, Zhang Peng, Guo Hui, Shi Juan, Liu Shilian, Liu Yanxin, Zheng Dexian
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Institute of Biomedical and Health Engineering Shenzhen Institutes of Advanced Technology, CAS, China.
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
Mol Oncol. 2015 Apr;9(4):806-17. doi: 10.1016/j.molonc.2014.12.004. Epub 2014 Dec 30.
Macrophages are responsible for defending against diverse pathogens and play a crucial role in the innate immune system. Macrophage's lifespan is determined by homeostatic balance between survival and apoptosis. Here we report that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers both apoptosis and autophagy in human U937 cells. Inhibition of autophagy facilitates TRAIL-induced apoptosis, suggesting that autophagy of macrophages protects against TRAIL-induced apoptosis. TRAIL treatment influences the expression of death receptors, indicating that TRAIL-induced apoptosis and autophagy are mediated by death receptors. RIP1 ubiquitination and expression regulate apoptosis and autophagy. Furthermore, expression and bioactivity of the p43/41-caspase-8 variant are critical to TRAIL-induced autophagy and apoptosis. Knockdown of RIP1 suppresses autophagy in macrophage. These data demonstrate that RIP1 is essential for the regulation of death receptor mediated autophagy and apoptosis. The results in this study contribute to understanding the regulation of autophagy and apoptosis in macrophages, and shed lights on death receptor-targeted therapy for cancer, inflammation and autoimmune diseases.
巨噬细胞负责抵御多种病原体，在固有免疫系统中发挥关键作用。巨噬细胞的寿命由生存与凋亡之间的稳态平衡决定。在此我们报告，肿瘤坏死因子相关凋亡诱导配体（TRAIL）在人U937细胞中触发凋亡和自噬。自噬的抑制促进TRAIL诱导的凋亡，表明巨噬细胞的自噬可抵御TRAIL诱导的凋亡。TRAIL处理会影响死亡受体的表达，表明TRAIL诱导的凋亡和自噬由死亡受体介导。RIP1泛素化和表达调节凋亡和自噬。此外，p43/41 - 半胱天冬酶 - 8变体的表达和生物活性对TRAIL诱导的自噬和凋亡至关重要。敲低RIP1可抑制巨噬细胞中的自噬。这些数据表明，RIP1对于死亡受体介导的自噬和凋亡的调节至关重要。本研究结果有助于理解巨噬细胞中自噬和凋亡的调节，并为癌症、炎症和自身免疫性疾病的死亡受体靶向治疗提供线索。
