IKK-dependent, NF-B-independent control of autophagic gene expression.
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The induction of mammalian autophagy, a cellular catabolic bulk-degradation process conserved from humans to yeast, was recently shown to require IB kinase (IKK), the upstream regulator of the nuclear factor (NF)-B pathway. Interestingly, it was shown that this response did not involve NF-B. Thus, the mechanism by which IKK promotes stimulus-induced autophagy is largely unknown. Here, we investigate the role of IKK/NF-B in response to nutrient deprivation, the well-understood autophagy-inducing stimulus. IKK and both the classic and non-canonical pathways of NF-B are robustly induced in response to cellular starvation. Notably, cells lacking either catalytic subunit of IKK (IKK- or IKK-) fail to induce autophagy in response to cellular starvation. Importantly, we show that IKK activity but not NF-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-B subunits are dispensable for both basal and starvation-induced expression of proautophagic genes. However, starvation-induced activation of NF-B is not inconsequential, as increases in expression of antiapoptotic NF-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-B-dependent antiapoptotic gene expression as well as controlling expression of autophagic genes through a yet undetermined mechanism.
author list (cited authors)
Comb, W. C., Cogswell, P., Sitcheran, R., & Baldwin, A. S.
complete list of authors
Comb, WC||Cogswell, P||Sitcheran, R||Baldwin, AS