贸易
坏死性下垂
裂谷1
细胞生物学
时尚
特里夫
信号转导
促炎细胞因子
肿瘤坏死因子α
生物
程序性细胞死亡
化学
细胞凋亡
免疫学
死亡域
炎症
半胱氨酸蛋白酶
生物化学
受体
先天免疫系统
Toll样受体
作者
Maria Feoktistova,Roman Makarov,Amir S. Yazdi,Diana Panayotova-Dimitrova
标识
DOI:10.3390/ijms222212459
摘要
TNF is a proinflammatory cytokine that is critical for the coordination of tissue homeostasis. RIPK1 and TRADD are the main participants in the transduction of TNF signaling. However, data on the cell fate-controlling functions of both molecules are quite controversial. Here, we address the functions of RIPK1 and TRADD in TNF signaling by generating RIPK1- or TRADD-deficient human cell lines. We demonstrate that RIPK1 is relevant for TNF-induced apoptosis and necroptosis in conditions with depleted IAPs. In addition, TRADD is dispensable for necroptosis but required for apoptosis. We reveal a new possible function of TRADD as a negative regulator of NIK stabilization and subsequent ripoptosome formation. Furthermore, we show that RIPK1 and TRADD do not appear to be essential for the activation of MAPK signaling. Moreover, partially repressing NF-κB activation in both RIPK1 and TRADD KO cells does not result in sensitization to TNF alone due to the absence of NIK stabilization. Importantly, we demonstrate that RIPK1 is essential for preventing TRADD from undergoing TNF-induced ubiquitination and degradation. Taken together, our findings provide further insights into the specific functions of RIPK1 and TRADD in the regulation of TNF-dependent signaling, which controls the balance between cell death and survival.
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