State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai, China.
Psychiatry and Inflammation Program, Department of Psychiatry, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA.
FEBS J. 2017 Mar;284(6):948-966. doi: 10.1111/febs.14026. Epub 2017 Feb 20.
Tryptophan is metabolized along the kynurenine and serotonin pathways, resulting in formation of kynurenine metabolites, neuroactive serotonin and melatonin. Each pathway is critical for maintaining healthy homeostasis. However, the two pathways are extremely unequal in their ability to degrade tryptophan, and little is known about the mechanisms maintaining the balance between them. Here, we demonstrated that in PC12 cells, a change of expression of key genes of one pathway resulted in a change of expression of key genes of the other. Melatonin, the end product of the serotonin pathway, played an important role in tryptophan metabolism by affecting both key enzymes of the two pathways. Melatonin treatment induced the expression of indole-2,3-dioxygenase 1 (IDO1) and enhanced the activity of the IDO1 promoter while decreasing the expression of arylalkylamine N-acetyl transferase. Melatonin treatment up-regulated the expression of forkhead box protein O1 (FoxO1) and enhanced the binding of FoxO1 to the IDO1 promoter. FoxO1 was shown to be a new regulator for IDO1 expression. Melatonin treatment decreased the phosphorylation of FoxO1 by extracellular signal-regulated kinases 1 and 2 and protein kinase B (Akt) and increased the phosphorylation of binding protein 14-3-3 by c-Jun N-terminal kinase (JNK), and thus the complex of FoxO1-14-3-3 in the cytoplasm was disassembled and FoxO1 was relocated to the nucleus to induce IDO1 expression. The JNK signaling pathway played an important role in melatonin-induced IDO1 up-regulation. In conclusion, this study suggests a link between melatonin, JNK, FoxO1 and IDO1 that acts as a potential balance regulator of tryptophan metabolism, and offers a new approach to treat diseases related to dysregulation of tryptophan metabolism.
色氨酸沿着犬尿酸和血清素途径代谢，导致犬尿酸代谢物、神经活性血清素和褪黑素的形成。每条途径对于维持健康的体内平衡都至关重要。然而，这两条途径在降解色氨酸的能力上极不平衡，关于维持它们之间平衡的机制知之甚少。在这里，我们证明在 PC12 细胞中，一条途径的关键基因表达的变化导致另一条途径的关键基因表达的变化。褪黑素，即血清素途径的终产物，通过影响两条途径的关键酶，在色氨酸代谢中发挥重要作用。褪黑素处理诱导吲哚-2,3-双加氧酶 1（IDO1）的表达，并增强 IDO1 启动子的活性，同时降低芳基烷基胺 N-乙酰转移酶的表达。褪黑素处理上调叉头框蛋白 O1（FoxO1）的表达，并增强 FoxO1 与 IDO1 启动子的结合。FoxO1 被证明是 IDO1 表达的新调节因子。褪黑素处理通过细胞外信号调节激酶 1 和 2（ERK1/2）和蛋白激酶 B（Akt）降低 FoxO1 的磷酸化，并增加 c-Jun N-末端激酶（JNK）结合蛋白 14-3-3 的磷酸化，从而使细胞质中的 FoxO1-14-3-3 复合物解体，FoxO1 被重新定位到细胞核，诱导 IDO1 表达。JNK 信号通路在褪黑素诱导的 IDO1 上调中发挥重要作用。总之，本研究表明褪黑素、JNK、FoxO1 和 IDO1 之间存在联系，作为色氨酸代谢潜在的平衡调节剂，为治疗与色氨酸代谢失调相关的疾病提供了新的方法。
