Autophagy is required for the activation of NFκB

Cell Cycle. 2012 Jan 1;11(1):194-9. doi: 10.4161/cc.11.1.18669. Epub 2012 Jan 1.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy*
  • Autophagy-Related Protein 5
  • Autophagy-Related Protein 7
  • Beclin-1
  • Cell Line, Tumor
  • DNA Damage
  • Enzyme Activation
  • Humans
  • I-kappa B Kinase / metabolism
  • I-kappa B Proteins / metabolism
  • Mice
  • Microtubule-Associated Proteins / antagonists & inhibitors
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vesicular Transport Proteins / antagonists & inhibitors
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Atg5 protein, mouse
  • Atg7 protein, mouse
  • Autophagy-Related Protein 5
  • Beclin-1
  • Becn1 protein, mouse
  • I-kappa B Proteins
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • Vesicular Transport Proteins
  • Vps35 protein, mouse
  • NF-KappaB Inhibitor alpha
  • I-kappa B Kinase
  • Autophagy-Related Protein 7