IKK-dependent, NF-κB-independent control of autophagic gene expression

The induction of mammalian autophagy, a cellular catabolic bulk-degradation process conserved from humans to yeast, was recently shown to require I kappa B kinase (IKK), the upstream regulator of the nuclear factor (NF)-kappa B pathway. Interestingly, it was shown that this response did not involve NF-kappa B. Thus, the mechanism by which IKK promotes stimulus-induced autophagy is largely unknown. Here, we investigate the role of IKK/NF-kappa B in response to nutrient deprivation, the well-understood autophagy-inducing stimulus. IKK and both the classic and non-canonical pathways of NF-kappa B are robustly induced in response to cellular starvation. Notably, cells lacking either catalytic subunit of IKK (IKK-alpha or IKK-beta) fail to induce autophagy in response to cellular starvation. Importantly, we show that IKK activity but not NF-kappa B controls basal expression of the proautophagic gene LC3. We further demonstrate that starvation induces the expression of LC3 and two other essential autophagic genes ATG5 and Beclin-1 in an IKK-dependent manner. These results indicate that the IKK complex is a central mediator of starvation-induced autophagy in mammalian cells, and suggest that this requirement occurs at least in part through the regulation of autophagic gene expression. Interestingly, NF-kappa B subunits are dispensable for both basal and starvation-induced expression of proautophagic genes. However, starvation-induced activation of NF-kappa B is not inconsequential, as increases in expression of antiapoptotic NF-kappa B target genes such as Birc3 are observed in response to cellular starvation. Thus, IKK likely has multiple roles in response to starvation by regulating NF-kappa B-dependent antiapoptotic gene expression as well as controlling expression of autophagic genes through a yet undetermined mechanism. Oncogene (2011) 30, 1727-1732; doi:10.1038/onc.2010.553; published online 13 December 2010