RFX transcription factor DAF-19 regulates 5-HT and innate immune responses to pathogenic bacteria in Caenorhabditis elegans.
RFX transcription factor DAF-19 regulates 5-HT and innate immune responses to pathogenic bacteria in Caenorhabditis elegans.
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DOI：
10.1371/journal.pgen.1003324
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Sze JY
中科院分区：
文献类型：
--
作者：
Xie Y;Moussaif M;Choi S;Xu L;Sze JY
在秀丽隐杆线虫中，Toll-白细胞介素受体结构域接头蛋白TIR-1通过保守的丝裂原活化蛋白激酶（MAPK）信号级联诱导先天免疫，并上调一对ADF化学感受神经元中的5-HT生物合成基因tph-1以响应感染。在这里，我们确定了TIR-1信号通路下游的转录因子。我们发现，共同的转录因子控制先天免疫和5-HT的生物合成。我们证明了TIR-1蛋白的HEAT/Arm重复区的ARM基序中的半胱氨酸到酪氨酸的取代赋予TIR-1超活化，导致ADF神经元中的组成性tph-1上调，增加肠道抗菌基因的表达，并增强对人类机会致病菌铜绿假单胞菌PA 14的抵抗力。对过度活跃的TIR-1的抑制因子的正向遗传筛选导致了对调节因子X（RFX）转录因子的直系同源物的鉴定，调节因子X（RFX）转录因子是人类适应性免疫所需的。我们发现，转录激活因子（ATF）/cAMP反应元件结合B（CREB）家族的转录因子ATF-7的音乐会，调节tph-1和抗菌基因，让人想起RFX-CREB在人类免疫细胞中的相互作用。daf-19突变体显示出对PA 14杀伤的高度敏感性。值得注意的是，尽管肠道免疫中的TIR-1-MAPK-tPh-19/ATF-7途径由DKF-2/蛋白激酶D调节，但我们发现tph-1表达的调节不依赖于DKF-2，而是需要Ca 2 +/钙调蛋白依赖性蛋白激酶（CaMK）II。我们的研究结果表明，致病线索触发一个共同的核心信号通路，通过组织特异性机制，并表现出一种新的作用RFX因子在神经元和先天性免疫反应感染。Toll-白细胞介素受体（TIR）-结构域衔接蛋白是激活信号级联的关键，在进化上不同的生物体中诱导对内部和外部致病信号的转录反应。尽管缺乏哺乳动物先天免疫转录调节因子核因子-κ B（NF-κB）的同源物，线虫秀丽隐杆线虫通过激活先天免疫系统和神经元中的TIR-1信号传导靶点来响应感染。通过对TIR-1信号传导上调5-羟色胺生物合成基因tph-1所需的因子进行遗传筛选，我们鉴定出了一种调节因子X（RFX）转录因子的直系同源物，最初在人类免疫细胞中发现。我们发现，在细菌感染时，EAE-19与转录因子激活因子（ATF）/cAMP反应元件结合B（CREB）家族成员ATF-7协同上调ADF化学感受神经元中的tph-1和肠道中的抗菌基因，这让人联想到人类免疫细胞中的RFX-CREB相互作用。daf-19突变体显示出对人类病原体铜绿假单胞菌PA 14的杀伤的高度敏感性。我们的研究表明，RFX转录调控，这是人类获得性免疫所必需的，在控制5-羟色胺的生物合成和先天免疫中具有古老的作用。
In Caenorhabditis elegans the Toll-interleukin receptor domain adaptor protein TIR-1 via a conserved mitogen-activated protein kinase (MAPK) signaling cascade induces innate immunity and upregulates serotonin (5-HT) biosynthesis gene tph-1 in a pair of ADF chemosensory neurons in response to infection. Here, we identify transcription factors downstream of the TIR-1 signaling pathway. We show that common transcription factors control the innate immunity and 5-HT biosynthesis. We demonstrate that a cysteine to tyrosine substitution in an ARM motif of the HEAT/Arm repeat region of the TIR-1 protein confers TIR-1 hyperactivation, leading to constitutive tph-1 upregulation in the ADF neurons, increased expression of intestinal antimicrobial genes, and enhanced resistance to killing by the human opportunistic pathogen Pseudomonas aeruginosa PA14. A forward genetic screen for suppressors of the hyperactive TIR-1 led to the identification of DAF-19, an ortholog of regulatory factor X (RFX) transcription factors that are required for human adaptive immunity. We show that DAF-19 concerts with ATF-7, a member of the activating transcription factor (ATF)/cAMP response element-binding B (CREB) family of transcription factors, to regulate tph-1 and antimicrobial genes, reminiscent of RFX-CREB interaction in human immune cells. daf-19 mutants display heightened susceptibility to killing by PA14. Remarkably, whereas the TIR-1-MAPK-DAF-19/ATF-7 pathway in the intestinal immunity is regulated by DKF-2/protein kinase D, we found that the regulation of tph-1 expression is independent of DKF-2 but requires UNC-43/Ca2+/calmodulin-dependent protein kinase (CaMK) II. Our results suggest that pathogenic cues trigger a common core-signaling pathway via tissue-specific mechanisms and demonstrate a novel role for RFX factors in neuronal and innate immune responses to infection. Toll-interleukin receptor (TIR)–domain adaptor proteins are keys to activate signaling cascades inducing transcriptional responses to internal and external pathogenic signals in evolutionary disparate organisms. Despite lacking a homolog of the mammalian innate immunity transcriptional regulator nuclear factor-kappaB (NF-κB), the nematode Caenorhabditis elegans responds to infections by activating TIR-1 signaling targets in the innate immune system and in neurons. Through a genetic screen for factors required for TIR-1 signaling to upregulate the serotonin biosynthesis gene tph-1, we identified DAF-19, an ortholog of regulatory factor X (RFX) transcription factors that were initially discovered in human immune cells. We show that DAF-19 concerts with ATF-7, a member of the activating transcription factor (ATF)/cAMP response element-binding B (CREB) family of transcription factors, to upregulate tph-1 in the ADF chemosensory neurons and antimicrobial genes in the intestine in response to bacterial infection, reminiscent of RFX-CREB interaction in human immune cells. daf-19 mutants display heightened susceptibility to killing by the human pathogen Pseudomonas aeruginosa PA14. Our studies suggest that RFX transcriptional regulation, which is essential for human adaptive immunity, has an ancient role in controlling serotonin biosynthesis and innate immunity.
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DOI：
10.1523/jneurosci.0044-09.2009
发表时间：
2009-04-01
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Moussaif M;Sze JY
通讯作者：
Sze JY
影响因子：
30.8
作者：
Jansen, G;Thijssen, KL;Plasterk, RHA
通讯作者：
Plasterk, RHA
影响因子：
10.7
作者：
Amoutzias, G. D.;Veron, A. S.;Robertson, D. L.
通讯作者：
Robertson, D. L.
影响因子：
15.3
作者：
Kim, Younghwa;Zhou, Ping;Ding, Aihao
通讯作者：
Ding, Aihao
DOI：
10.1016/j.bbrc.2007.08.190
发表时间：
2007-11-16
影响因子：
3.1
作者：
Kurz, C. Leopold;Shapira, Michael;Tan, Man-Wah
通讯作者：
Tan, Man-Wah