Abstract
The induction of mammalian autophagy, a cellular catabolic bulk-degradation process conserved from humans to yeast, was recently shown to require IκB kinase (IKK), the upstream regulator of the nuclear factor (NF)-κB pathway. Interestingly, it was shown that this response did not involve NF-κB. Thus, the mechanism by which IKK promotes stimulus-induced autophagy is largely unknown. Here, we investigate the role of IKK/NF-κB in response to nutrient deprivation, the well-understood autophagy-inducing stimulus. IKK and both the classic and non-canonical pathways of NF-κB are robustly induced in response to cellular starvation. Notably, cells lacking either catalytic subunit of IKK (IKK-α or IKK-β) fail to induce autophagy in response to cellular starvation. Importantly, we show that IKK activity but not NF-κB 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-κB subunits are dispensable for both basal and starvation-induced expression of proautophagic genes. However, starvation-induced activation of NF-κB is not inconsequential, as increases in expression of antiapoptotic NF-κB 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-κB-dependent antiapoptotic gene expression as well as controlling expression of autophagic genes through a yet undetermined mechanism.
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Acknowledgements
We are grateful to Dr Alexander Hoffmann for the p65/c-Rel DKO cells and to Dr Denis Guttridge for the RelB−/− and p52−/− cells. We thank members of the Baldwin lab for thoughtful discussion and manuscript feedback. Research support was provided by NIH grants CA75080, AI035098, CA73756 and the Waxman Cancer Research Foundation.
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Comb, W., Cogswell, P., Sitcheran, R. et al. IKK-dependent, NF-κB-independent control of autophagic gene expression. Oncogene 30, 1727–1732 (2011). https://doi.org/10.1038/onc.2010.553
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DOI: https://doi.org/10.1038/onc.2010.553
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