Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Road, PuDong District, 201210, Shanghai, China.
University of Chinese Academy of Sciences, 100049, Beijing, China.
Cell Death Dis. 2022 Sep 7;13(9):773. doi: 10.1038/s41419-022-05206-9.
Activation of TNFR1 by TNFα induces the formation of a membrane-associated, intracellular complex termed complex I. Complex I orchestrates a complex pattern of modifications on key regulators of TNF signaling that collectively determines the cell fate by activating pro-survival or executing cell death programs. However, the regulatory mechanism of complex I in cell-fate decision is not fully understood. Here we identify protein phosphatase-6 (PP6) as a previously unidentified component of complex I. Loss of PP6 protects cells from TNFα-mediated cell death. The role of PP6 in regulating cell death requires its phosphatase activity and regulatory subunits. Further mechanistic studies show that PP6 modulates LUBAC-mediated M1-ubiquitination of RIPK1 and c-FLIP to promote RIPK1 activation and c-FLIP degradation. We also show that melanoma-associated PP6 inactivating mutants offer resistance to cell death due to the loss of sensitivity to TNFα. Thus, our study provides a potential mechanism by which melanoma-related PP6 inactivating mutations promote cancer progression.
肿瘤坏死因子受体 1（TNFR1）被肿瘤坏死因子-α（TNFα）激活后，会形成一个称为复合物 I 的膜相关的细胞内复合物。复合物 I 协调了 TNF 信号转导关键调节因子的一系列复杂修饰，通过激活抗凋亡或执行细胞死亡程序，共同决定细胞命运。然而，复合物 I 在细胞命运决定中的调控机制尚不完全清楚。在这里，我们鉴定出蛋白磷酸酶-6（PP6）是复合物 I 的一个以前未被识别的组成部分。PP6 的缺失可保护细胞免受 TNFα 诱导的细胞死亡。PP6 在调节细胞死亡中的作用需要其磷酸酶活性和调节亚基。进一步的机制研究表明，PP6 调节 LUBAC 介导的 RIPK1 和 c-FLIP 的 M1-泛素化，以促进 RIPK1 的激活和 c-FLIP 的降解。我们还表明，由于对 TNFα 的敏感性降低，黑色素瘤相关的失活突变的 PP6 提供了对细胞死亡的抗性。因此，我们的研究提供了一种潜在的机制，即黑色素瘤相关的 PP6 失活突变促进癌症的进展。
