Chang Lufen, Kamata Hideaki, Solinas Giovanni, Luo Jun-Li, Maeda Shin, Venuprasad K, Liu Yun-Cai, Karin Michael
Division of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, City of Hope National Medical Center, 1500 E. Duarte Road, KCRB 3009, Duarte, CA 91010, USA.
Cell. 2006 Feb 10;124(3):601-13. doi: 10.1016/j.cell.2006.01.021.
The proinflammatory cytokine tumor necrosis factor (TNF) alpha signals both cell survival and death. The biological outcome of TNFalpha treatment is determined by the balance between NF-kappaB and Jun kinase (JNK) signaling; NF-kappaB promotes survival, whereas JNK enhances cell death. Critically, identity of a JNK substrate that promotes TNFalpha-induced apoptosis has been outstanding. Here we show that TNFalpha-mediated JNK activation accelerates turnover of the NF-kappaB-induced antiapoptotic protein c-FLIP, an inhibitor of caspase-8. This is not due to direct c-FLIP phosphorylation but depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation. JNK1 or Itch deficiency or treatment with a JNK inhibitor renders mice resistant in three distinct models of TNFalpha-induced acute liver failure, and cells from these mice do not display inducible c-FLIP(L) ubiquitination and degradation. Thus, JNK antagonizes NF-kappaB during TNFalpha signaling by promoting the proteasomal elimination of c-FLIP(L).
促炎细胞因子肿瘤坏死因子（TNF）α既能发出细胞存活信号，也能发出细胞死亡信号。TNFα治疗的生物学结果取决于核因子κB（NF-κB）和c-Jun氨基末端激酶（JNK）信号之间的平衡；NF-κB促进存活，而JNK增强细胞死亡。至关重要的是，促进TNFα诱导的细胞凋亡的JNK底物的身份一直未明。在此，我们表明TNFα介导的JNK激活加速了NF-κB诱导的抗凋亡蛋白c-FLIP（一种半胱天冬酶-8抑制剂）的周转。这并非由于c-FLIP的直接磷酸化，而是取决于JNK介导的E3泛素连接酶Itch的磷酸化和激活，Itch特异性地使c-FLIP泛素化并诱导其蛋白酶体降解。JNK1或Itch缺陷，或用JNK抑制剂治疗，可使小鼠在三种不同的TNFα诱导的急性肝衰竭模型中具有抗性，并且来自这些小鼠的细胞不会表现出可诱导的c-FLIP(L)泛素化和降解。因此，JNK在TNFα信号传导过程中通过促进c-FLIP(L)的蛋白酶体清除来拮抗NF-κB。
