Institute of Biology, Leiden University, Sylviusweg 72, 2333 BE, Leiden, The Netherlands.
Radboud Institute for Molecular Life Sciences - Tumour immunology department, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Sci Rep. 2017 Aug 4;7(1):7327. doi: 10.1038/s41598-017-07116-9.
Autophagy is an evolutionarily conserved process that degrades cellular components to restore energy homeostasis under limited nutrient conditions. How this starvation-induced autophagy is regulated at the whole-body level is not fully understood. Here, we show that the tumor suppressor Lkb1, which activates the key energy sensor AMPK, also regulates starvation-induced autophagy at the organismal level. Lkb1-deficient zebrafish larvae fail to activate autophagy in response to nutrient restriction upon yolk termination, shown by reduced levels of the autophagy-activating proteins Atg5, Lc3-II and Becn1, and aberrant accumulation of the cargo receptor and autophagy substrate p62. We demonstrate that the autophagy defect in lkb1 mutants can be partially rescued by inhibiting mTOR signaling but not by inhibiting the PI3K pathway. Interestingly, mTOR-independent activation of autophagy restores degradation of the aberrantly accumulated p62 in lkb1 mutants and prolongs their survival. Our data uncover a novel critical role for Lkb1 in regulating starvation-induced autophagy at the organismal level, providing mechanistic insight into metabolic adaptation during development.
自噬是一种进化上保守的过程，它可以在营养有限的条件下降解细胞成分，以恢复能量稳态。但目前尚不完全清楚这种饥饿诱导的自噬是如何在全身水平上进行调节的。在这里，我们发现肿瘤抑制因子 Lkb1 通过激活关键的能量传感器 AMPK，也可以在机体水平上调节饥饿诱导的自噬。当卵黄结束时，Lkb1 缺失的斑马鱼幼虫不能对营养限制做出反应，从而激活自噬，这表现为自噬激活蛋白 Atg5、Lc3-II 和 Becn1 的水平降低，以及货物受体和自噬底物 p62 的异常积累。我们证明，通过抑制 mTOR 信号通路而不是抑制 PI3K 通路，部分挽救了 lkb1 突变体中的自噬缺陷。有趣的是，mTOR 非依赖性自噬的激活恢复了 lkb1 突变体中异常积累的 p62 的降解，并延长了它们的存活时间。我们的数据揭示了 Lkb1 在调节机体水平饥饿诱导自噬方面的新的关键作用，为发育过程中的代谢适应提供了机制上的见解。
