INSERM, U848, Villejuif, France.
Cell Cycle. 2012 Jan 1;11(1):194-9. doi: 10.4161/cc.11.1.18669.
It is well-established that the activation of the inhibitor of NFκB (IκBα) kinase (IKK) complex is required for autophagy induction by multiple stimuli. Here, we show that in autophagy-competent mouse embryonic fibroblasts (MEFs), distinct autophagic triggers, including starvation, mTOR inhibition with rapamycin and p53 inhibition with cyclic pifithrin α lead to the activation of IKK, followed by the phosphorylation-dependent degradation of IκBα and nuclear translocation of NFκB. Remarkably, the NFκB signaling pathway was blocked in MEFs lacking either the essential autophagy genes Atg5 or Atg7. In addition, we found that tumor necrosis factor α (TNFα)-induced NFκB nuclear translocation is abolished in both Atg5- and Atg7-deficient MEFs. Similarly, the depletion of essential autophagy modulators, including ATG5, ATG7, Beclin 1 and VPS34, by RNA interference inhibited TNFα-driven NFκB activation in two human cancer cell lines. In conclusion, it appears that, at least in some instances, autophagy is required for NFκB activation, highlighting an intimate crosstalk between these two stress response signaling pathways.
已有充分证据表明，多种刺激诱导自噬发生所必需的是 NFκB（IκBα）激酶（IKK）复合物的激活。在这里，我们发现，在自噬功能正常的小鼠胚胎成纤维细胞（MEFs）中，不同的自噬触发物，包括饥饿、雷帕霉素抑制 mTOR 和环化 pifithrin α 抑制 p53，都会导致 IKK 的激活，随后 IκBα的磷酸化依赖性降解和 NFκB 的核转位。值得注意的是，在缺乏必需的自噬基因 Atg5 或 Atg7 的 MEFs 中，NFκB 信号通路被阻断。此外，我们发现 TNFα 诱导的 NFκB 核转位在 Atg5 和 Atg7 缺陷型 MEFs 中均被消除。同样，通过 RNA 干扰耗尽必需的自噬调节剂，包括 ATG5、ATG7、Beclin 1 和 VPS34，也抑制了两种人类癌细胞系中 TNFα 驱动的 NFκB 激活。总之，至少在某些情况下，自噬对于 NFκB 的激活是必需的，这突显了这两种应激反应信号通路之间的密切相互作用。
