An intraflagellar transport dependent negative feedback regulates the MAPKKK DLK-1 to protect cilia from degeneration.
An intraflagellar transport dependent negative feedback regulates the MAPKKK DLK-1 to protect cilia from degeneration.
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DOI：
10.1073/pnas.2302801120
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发表时间：
2023-09-26
影响因子：
11.1
通讯作者：
Jin, Yishi
中科院分区：
文献类型：
--
作者：
Sun, Yue;Jin, Yishi
在不同的应激条件下，神经元需要分子的区隔作用来维持功能。保守的MAPKKK DLKs因其在突触和轴突中的作用而被广泛研究。然而，它们在其他神经元室中的功能尚未得到很好的探索。在这里，我们确定了一种机制，通过鞭毛内运输（IFT）积极抑制秀丽隐杆线虫DLK-1在纤毛感觉神经元中的积累。IFT的中断激活DLK-1并增加其下游转录因子CEBP-1的表达，进而抑制DLK-1的转录。这种依赖于ift的DLK-1负反馈调节在纤毛变性中发挥保护作用。我们的发现揭示了调节感觉神经元中DLK-1信号的稳态机制。初级纤毛是支持细胞和生物体发育和功能的特化细胞器。鞭毛内运输（IFT）对纤毛的形成、维持和功能至关重要。在秀丽隐杆线虫纤毛感觉神经元中，IFT与信号分子相互作用产生不同的形态和功能特征，并维持纤毛的完整性。在这里，我们报告了一种依赖于ift的反馈控制在纤毛感觉神经元中保守的MAPKKK DLK-1。众所周知，DLK蛋白在突触形成、轴突再生和退化中起作用，但它们在其他神经元室中的作用尚未得到充分研究。通过对内源性标记的DLK-1表达改变的正向遗传筛选，我们发现了多个在缺陷感觉末梢中显示DLK-1积累增加的ift突变体。我们表明，在急性IFT中断的反应中，DLK-1迅速且可逆地积累。转录因子CEBP-1的表达水平在ift突变体的纤毛感觉神经元中也有所增加。已知CEBP-1在DLK-1的下游作用，参与突触和轴突的发育和维持。有趣的是，CEBP-1表达的调控显示感觉神经元类型依赖于DLK-1。此外，在纤毛形态复杂的感觉神经元AWC中，上调的CEBP-1在转录水平上抑制DLK-1，从而抑制DLK-1的积累。最后，ift依赖的DLK-1和CEBP-1调节回路在纤毛变性模型中提供神经保护。这些发现揭示了一种监视机制，在这种机制中，严格控制DLK-1信号以特定环境的方式保护纤毛的完整性。
Neurons require compartmentalized actions of molecules to sustain function under various stress conditions. The conserved MAPKKK DLKs are key stress-sensing kinases extensively studied for their roles in synapses and axons. However, their function in other neuronal compartments is not well explored. Here, we identified a mechanism by which intraflagellar transport (IFT) actively represses accumulation of C. elegans DLK-1 in the ciliated sensory neurons. Disruption in IFT activates DLK-1 and increases expression of its downstream transcription factor CEBP-1, which in turn represses dlk-1 transcription. This IFT-dependent negative feedback regulation of DLK-1 offers protective roles in cilia undergoing degeneration. Our findings uncovered a homeostatic mechanism regulating DLK-1 signaling in sensory neurons. Primary cilia are specialized organelles supporting the development and function of cells and organisms. Intraflagellar transport (IFT) is essential for cilia formation, maintenance, and function. In C. elegans ciliated sensory neurons, IFT interacts with signaling molecules to generate distinct morphological and function features and also to maintain the integrity of cilia. Here, we report an IFT-dependent feedback control on the conserved MAPKKK DLK-1 in the ciliated sensory neurons. DLK proteins are widely known to act in synapse formation, axon regeneration, and degeneration, but their roles in other neuronal compartments are understudied. By forward genetic screening for altered expression of the endogenously tagged DLK-1 we identified multiple ift mutants showing increased DLK-1 accumulation in the defective sensory endings. We show that in response to acute IFT disruption, DLK-1 accumulates rapidly and reversibly. The expression levels of the transcription factor CEBP-1, known to act downstream of DLK-1 in the development and maintenance of synapses and axons, are also increased in the ciliated sensory neurons of ift mutants. Interestingly, the regulation of CEBP-1 expression shows sensory neuron-type dependency on DLK-1. Moreover, in the sensory neuron AWC, which has elaborate cilia morphology, up-regulated CEBP-1 represses DLK-1 at the transcription level, thereby dampening DLK-1 accumulation. Last, the IFT-dependent regulatory loop of DLK-1 and CEBP-1 offers neuroprotection in a cilia degeneration model. These findings uncover a surveillance mechanism in which tight control on the DLK-1 signaling protects cilia integrity in a context-specific manner.
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DOI：
10.1073/pnas.2207134119
发表时间：
2022-08-23
影响因子：
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