Autophagy is required for the activation of NFκB

It is well-established that the activation of the inhibitor of NF kappa B (I kappa B alpha) 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 alpha, lead to the activation of IKK, followed by the phosphorylation-dependent degradation of I kappa B alpha and nuclear translocation of NF kappa B. Remarkably, the NF kappa B signaling pathway was blocked in MEFs lacking either the essential autophagy genes Atg5 or Atgh7. In addition, we found that tumor necrosis factor a (TNF alpha)-induced NF kappa B nuclear translaction is abolished in both Atg5- and Atg7-deficient MFFs. Similarly, the depletion of essential autophagy modulator, including Atg5, Atg7, Beclin 1 and VPS34, RNA interference inhibited TNG alpha-deriven NF kappa B activation in two human cancer cell lines. In conclusion, it appears that, at least in some instances, autophagy is required for NF kappa B activation, highlighting an intimate crosstalk between these two stress-response signaling pathways.