Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Oncogene. 2011 Apr 7;30(14):1727-32. doi: 10.1038/onc.2010.553. Epub 2010 Dec 13.
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.
哺乳动物自噬的诱导是一种从人类到酵母都保守的细胞内降解过程，最近的研究表明它需要 IκB 激酶 (IKK)，这是核因子 (NF)-κB 途径的上游调节剂。有趣的是，研究表明这种反应不涉及 NF-κB。因此，IKK 促进刺激诱导自噬的机制在很大程度上尚不清楚。在这里，我们研究了 IKK/NF-κB 在应对营养缺乏时的作用，这是一种众所周知的诱导自噬的刺激。IKK 和 NF-κB 的经典和非经典途径在细胞饥饿时都被强烈诱导。值得注意的是，缺乏 IKK 的任一催化亚基（IKK-α 或 IKK-β）的细胞在应对细胞饥饿时都不能诱导自噬。重要的是，我们表明 IKK 活性而不是 NF-κB 控制着自噬基因 LC3 的基础表达。我们进一步证明，饥饿以 IKK 依赖性方式诱导 LC3 和另外两个必需的自噬基因 ATG5 和 Beclin-1 的表达。这些结果表明 IKK 复合物是哺乳动物细胞饥饿诱导自噬的核心介质，并表明这种需求至少部分是通过调节自噬基因表达来实现的。有趣的是，NF-κB 亚基对于基础和饥饿诱导的自噬基因表达都是可有可无的。然而，NF-κB 的诱导激活并非无关紧要，因为在细胞饥饿时观察到抗凋亡 NF-κB 靶基因如 Birc3 的表达增加。因此，IKK 可能通过调节 NF-κB 依赖性抗凋亡基因表达以及通过尚未确定的机制控制自噬基因的表达，从而在应对饥饿时发挥多种作用。
