title: IKK-dependent, NF-κB-independent control of autophagic gene expression.
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.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Comb
authors.forename: P
authors.initials: P
authors.lastname: Cogswell
authors.forename: R
authors.initials: R
authors.lastname: Sitcheran
authors.forename: A S
authors.initials: AS
authors.lastname: Baldwin
mesh_terms: D000818:Animals; D001343:Autophagy; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D051550:I-kappa B Kinase / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D013217:Starvation / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D051550:I-kappa B Kinase