PDF(Pubmed)
Abstract：
Liver kinase B1 (LKB1), an evolutionarily conserved serine/threonine kinase, is a master regulator of the AMPK subfamily and controls cellular events such as polarity, proliferation, and energy homeostasis. Functions and mechanisms of the LKB1-AMPK axis at specific subcellular compartments, such as lysosome and mitochondria, have been established. AMPK is known to be activated at the Golgi; however, functions and regulatory mechanisms of the LKB1-AMPK axis at the Golgi apparatus remain elusive. Here, we show that TBC1D23, a Golgi-localized protein that is frequently mutated in the neurodevelopment disorder pontocerebellar hypoplasia (PCH), is specifically required for the LKB1 signaling at the Golgi. TBC1D23 directly interacts with LKB1 and recruits LKB1 to Golgi, promoting Golgi-specific activation of AMPK upon energy stress. Notably, Golgi-targeted expression of LKB1 rescues TBC1D23 deficiency in zebrafish models. Furthermore, the loss of LKB1 causes neurodevelopmental abnormalities in zebrafish, which partially recapitulates defects in TBC1D23-deficient zebrafish, and LKB1 sustains normal neuronal development via TBC1D23 interaction. Our study uncovers a regulatory mechanism of the LKB1 signaling, and reveals that a disrupted Golgi-LKB1 signaling underlies the pathogenesis of PCH.
摘要：
肝激酶B1(LKB1),一种进化保守的丝氨酸/苏氨酸激酶，是AMPK亚家族的主要调节因子，控制细胞事件，如极性，扩散,和能量稳态。LKB1-AMPK轴在特定亚细胞区室的功能和机制，比如溶酶体和线粒体，已经建立。已知AMPK在高尔基体被激活；然而，高尔基体上LKB1-AMPK轴的功能和调节机制仍然难以捉摸。这里,我们显示TBC1D23是一种高尔基定位蛋白，在神经发育障碍小脑发育不全（PCH）中经常发生突变，对于高尔基体处的LKB1信令是特别需要的。TBC1D23直接与LKB1相互作用，并将LKB1招募到高尔基，在能量胁迫下促进高尔基体特异性激活AMPK。值得注意的是,高尔基体靶向表达LKB1可挽救斑马鱼模型中的TBC1D23缺陷。此外，LKB1的缺失会导致斑马鱼的神经发育异常，部分概括了TBC1D23缺陷斑马鱼的缺陷，LKB1通过TBC1D23相互作用维持正常的神经元发育。我们的研究揭示了LKB1信号的调节机制，并揭示了Golgi-LKB1信号传导中断是PCH发病机理的基础。
