The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function in Caenorhabditis elegans.
The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function in Caenorhabditis elegans.
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DOI：
10.1371/journal.pgen.1003354
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发表时间：
2013-03
期刊：
影响因子：
4.5
通讯作者：
Sieburth D
中科院分区：
文献类型：
--
作者：
Staab TA;Griffen TC;Corcoran C;Evgrafov O;Knowles JA;Sieburth D
转录因子Nrf家族在介导对细胞应激的适应性反应和防御神经变性、衰老和癌症中起关键作用。在这里，我们报告了秀丽隐杆线虫NRF同系物SKN-1在调节神经肌肉接头（NMJ）的突触传递的新作用。通过用线粒体毒素亚砷酸钠进行急性药理学治疗或通过引起组成性SKN-1激活的突变来激活SKN-1，导致神经肌肉功能缺陷。此外，消除保守的WD 40重复蛋白WDR-23，SKN-1的主要负调节因子，导致运动和突触囊泡和胆碱能运动轴突的神经肽释放受损。使skn-1活性消失的突变恢复了wdr-23突变体和毒素处理动物的正常神经肌肉功能。我们发现，WDR-23在肠道中对SKN-1的负调节，而不是在神经肌肉接头处，对于适当的神经肌肉功能是必要的和足够的。WDR-23亚型差异定位于线粒体外膜和细胞核，WDR-23对神经肌肉功能的影响依赖于其与cullin E3泛素连接酶的相互作用。最后，wdr-23突变体的全转录组RNA测序揭示了已知SKN-1/Nrf 2调节的应激反应基因以及先前未参与SKN-1/Nrf 2反应的神经传递基因的表达增加。总之，我们的研究结果表明，SKN-1/Nrf 2激活可能是一种机制，通过这种机制，在一个组织中检测到的细胞应激通过内分泌信号传导影响远端组织的细胞功能。这些结果为SKN-1/Nrf 2如何保护神经系统免受氧化应激损伤提供了深入了解。转录程序控制细胞在面对环境应激时的反应，例如饮食限制、缺氧或氧化应激。此外，为了促进生物体响应于损伤的存活，必须建立组织之间的通信。利用模型系统C. elegans，我们调查的转录因子SKN-1介导的神经系统的功能变化。我们确定，SKN-1的激活，无论是遗传还是通过暴露于线粒体毒素亚砷酸盐，导致发生在神经肌肉接头的运动变化。此外，神经系统的这些变化是通过肠道的信号传导引起的。最后，我们使用全转录组RNA测序来鉴定可能影响运动行为的SKN-1的新转录靶点。我们的研究结果表明，神经元的功能可以在突触水平上调节，以响应环境应激。
The Nrf family of transcription factors plays a critical role in mediating adaptive responses to cellular stress and defends against neurodegeneration, aging, and cancer. Here, we report a novel role for the Caenorhabditis elegans Nrf homolog SKN-1 in regulating synaptic transmission at neuromuscular junctions (NMJs). Activation of SKN-1, either by acute pharmacological treatment with the mitochondrial toxin sodium arsenite or by mutations that cause constitutive SKN-1 activation, results in defects in neuromuscular function. Additionally, elimination of the conserved WD40 repeat protein WDR-23, a principal negative regulator of SKN-1, results in impaired locomotion and synaptic vesicle and neuropeptide release from cholinergic motor axons. Mutations that abolish skn-1 activity restore normal neuromuscular function to wdr-23 mutants and animals treated with toxin. We show that negative regulation of SKN-1 by WDR-23 in the intestine, but not at neuromuscular junctions, is necessary and sufficient for proper neuromuscular function. WDR-23 isoforms differentially localize to the outer membranes of mitochondria and to nuclei, and the effects of WDR-23 on neuromuscular function are dependent on its interaction with cullin E3 ubiquitin ligase. Finally, whole-transcriptome RNA sequencing of wdr-23 mutants reveals an increase in the expression of known SKN-1/Nrf2-regulated stress-response genes, as well as neurotransmission genes not previously implicated in SKN-1/Nrf2 responses. Together, our results indicate that SKN-1/Nrf2 activation may be a mechanism through which cellular stress, detected in one tissue, affects cellular function of a distal tissue through endocrine signaling. These results provide insight into how SKN-1/Nrf2 might protect the nervous system from damage in response to oxidative stress. Transcriptional programs control cellular responses in the face of environmental stress, such as dietary restriction, hypoxia, or oxidative stress. Furthermore, in order to promote survival of the organism in response to insult, communication between tissues must be established. Using the model system C. elegans, we investigate functional changes in the nervous system mediated by the transcription factor SKN-1. We establish that activation of SKN-1, either genetically or through exposure to the mitochondrial toxin arsenite, results in locomotion changes that take place at the neuromuscular junction. Furthermore, these changes in the nervous system are brought about through signaling from the intestine. Lastly, we use whole-transcriptome RNA sequencing to identify new transcriptional targets of SKN-1 that might be affecting locomotory behavior. Our results indicate that neuronal function can be regulated at the level of the synapse in response to environmental stress.
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