Sharma Vartika, Mutsuddi Mousumi, Mukherjee Ashim
Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
Cell Biol Int. 2021 Mar;45(3):686-700. doi: 10.1002/cbin.11521. Epub 2020 Dec 21.
JNK signaling is a highly conserved signaling pathway that regulates a broad spectrum of cellular processes including cell proliferation, migration, and apoptosis. In Drosophila, JNK signaling is activated by binding of the tumor necrosis factor (TNF) Eiger to its receptor Wengen, and a conserved signaling cascade operates that culminates into activation of dual phosphatase Puckered thereby triggering apoptosis. The tumor necrosis factor receptor (TNFR) associated factor 6 (TRAF6) is an adaptor protein, which transduces the signal from TNFRs and Toll-like receptor/interleukin-1 receptor superfamily to induce a wide spectrum of cellular responses. TRAF6 also acts as the adaptor protein that mediates Eiger/JNK signaling in Drosophila. In a genetic interaction study, deltex (Dx) was identified as a novel interactor of TRAF6. Dx is well known to regulate Notch signaling in a context-dependent manner. Our data suggest that combinatorial action of Dx and TRAF6 enhances the Dx-induced wing nicking phenotype by inducing caspase-mediated cell death. Co-expression of Dx and TRAF6 also results in enhanced invasive behavior and perturbs the normal morphology of cells. The cooperative action of Dx and TRAF6 is attributed to JNK activation, which also leads to ectopic wingless (Wg) and decapentaplegic (Dpp) expression. Our results also reveal that the endocytic pathway component Rab7 may play a pivotal role in the regulation of Dx-TRAF6-mediated activation of JNK signaling. Here, we present the fact that Dx and TRAF6 together activate JNK signaling in an Eiger-independent mechanism.
JNK信号通路是一条高度保守的信号通路，可调节广泛的细胞过程，包括细胞增殖、迁移和凋亡。在果蝇中，肿瘤坏死因子（TNF）艾格（Eiger）与其受体温根（Wengen）结合可激活JNK信号通路，并且会启动一个保守的信号级联反应，最终导致双磷酸酶褶皱（Puckered）激活，从而触发细胞凋亡。肿瘤坏死因子受体（TNFR）相关因子6（TRAF6）是一种衔接蛋白，它将来自TNFRs和Toll样受体/白细胞介素-1受体超家族的信号进行转导，以诱导广泛的细胞反应。TRAF6在果蝇中还作为介导艾格/JNK信号通路的衔接蛋白。在一项基因相互作用研究中，德尔泰克斯（Deltex，Dx）被鉴定为TRAF6的一种新型相互作用蛋白。众所周知，Dx以一种依赖于背景的方式调节Notch信号通路。我们的数据表明，Dx和TRAF6的联合作用通过诱导半胱天冬酶介导的细胞死亡增强了Dx诱导的翅刻痕表型。Dx和TRAF6的共表达还会导致侵袭行为增强并扰乱细胞的正常形态。Dx和TRAF6的协同作用归因于JNK激活，这也会导致异位无翅（Wingless，Wg）和五体不全（Decapentaplegic，Dpp）表达。我们的结果还揭示，内吞途径成分Rab7可能在调节Dx - TRAF6介导的JNK信号通路激活中起关键作用。在此，我们提出Dx和TRAF6共同以一种不依赖于艾格的机制激活JNK信号通路这一事实。
