TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin.
TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin.
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DOI：
10.1038/srep26566
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发表时间：
2016-05-25
影响因子：
4.6
通讯作者：
Nakamura A
中科院分区：
文献类型：
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作者：
Yabe-Wada T;Matsuba S;Takeda K;Sato T;Suyama M;Ohkawa Y;Takai T;Shi H;Philpott CC;Nakamura A
调节细胞因子的转录、翻译和分泌对于控制炎症的适当平衡至关重要。在这里，我们报告的分选受体分拣蛋白在细胞因子的产生中起着关键作用。我们观察到分拣蛋白与包括IFN-α在内的多种细胞因子的相互作用，并且分拣蛋白在浆细胞样树突状细胞（pDC）中的耗竭导致IFN-α分泌的减少，这表明分拣蛋白在pDC中IFN-α的胞吐运输中起关键作用。此外，分拣蛋白的mRNA被降解后，转录与各种TLR配体的刺激。多聚rC结合蛋白1（PCBP 1）可识别分拣蛋白mRNA 3′ UTR的富C元件（CRE），缺失PCBP 1可促进分拣蛋白转录本的降解，表明PCBP 1可作为反式作用因子稳定分拣蛋白转录本。PCBP 1的核苷酸结合能力被锌离子损害，细胞内锌的改变影响分拣蛋白的表达。因此，PCBP 1可能通过感应细胞内锌水平来控制分拣蛋白转录物的稳定性。总的来说，我们的研究结果提供了深入了解翻译后调节细胞因子的产生，通过转录后控制分拣蛋白的表达TLR信号。
Regulating the transcription, translation and secretion of cytokines is crucial for controlling the appropriate balance of inflammation. Here we report that the sorting receptor sortilin plays a key role in cytokine production. We observed interactions of sortilin with multiple cytokines including IFN-α, and sortilin depletion in plasmacytoid dendritic cells (pDCs) led to a reduction of IFN-α secretion, suggesting a pivotal role of sortilin in the exocytic trafficking of IFN-α in pDCs. Moreover, sortilin mRNA was degraded posttranscriptionally upon stimulation with various TLR ligands. Poly-rC-binding protein 1 (PCBP1) recognized the C-rich element (CRE) in the 3′ UTR of sortilin mRNA, and depletion of PCBP1 enhanced the degradation of sortilin transcripts, suggesting that PCBP1 can act as a trans-acting factor to stabilize sortilin transcripts. The nucleotide-binding ability of PCBP1 was impaired by zinc ions and alterations of intracellular zinc affect sortilin expression. PCBP1 may therefore control the stability of sortilin transcripts by sensing intracellular zinc levels. Collectively, our findings provide insights into the posttranslational regulation of cytokine production through the posttranscriptional control of sortilin expression by TLR signals.