Second messenger Ap(4)A polymerizes target protein HINT1 to transduce signals in Fc epsilon RI-activated mast cells
Second messenger Ap(4)A polymerizes target protein HINT1 to transduce signals in Fc epsilon RI-activated mast cells
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第二信使 Ap4A 聚合靶蛋白 HINT1，以在 FcepsilonRI 激活的肥大细胞中转导信号。
DOI：
10.1038/s41467-019-12710-8
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发表时间：
2019
影响因子：
16.6
通讯作者：
Wang Jing
中科院分区：
文献类型：
--
作者：
Yu Jing;Liu Zaizhou;Liang Yuanyuan;Luo Feng;Zhang Jie;Tian Cuiping;Motzik Alex;Zheng Mengmeng;Kang Jingwu;Zhong Guisheng;Liu Cong;Fang Pengfei;Guo Min;Razin Ehud;Wang Jing
信号转导系统使生物体能够监测其外部环境并相应地调整细胞过程。在肥大细胞中，第二信使Ap4A与组氨酸三联体核苷酸结合蛋白1 （HINT1）结合，破坏其与小眼相关转录因子（MITF）的相互作用，最终激活MITF下游基因的转录，以响应免疫刺激。HINT1蛋白如何识别Ap4A并受其调控尚不清楚。在这里，我们通过8种晶体结构、生化实验、阴性染色电镜和细胞实验，报告了Ap4A在溶液和活化的大鼠嗜碱性白血病细胞中特异性地聚合了HINT1。聚合界面与HINT1上的MITF相互作用区域重叠，表明可能存在一种竞争性机制来释放MITF以进行转录激活。其机制精确地取决于Ap4A的磷酸二酯链的长度。这些结果突出了第二信使的直接聚合信号机制。
Signal transduction systems enable organisms to monitor their external environments and accordingly adjust the cellular processes. In mast cells, the second messenger Ap4A binds to the histidine triad nucleotide-binding protein 1 (HINT1), disrupts its interaction with the microphthalmia-associated transcription factor (MITF), and eventually activates the transcription of genes downstream of MITF in response to immunostimulation. How the HINT1 protein recognizes and is regulated by Ap4A remain unclear. Here, using eight crystal structures, biochemical experiments, negative stain electron microscopy, and cellular experiments, we report that Ap4A specifically polymerizes HINT1 in solution and in activated rat basophilic leukemia cells. The polymerization interface overlaps with the area on HINT1 for MITF interaction, suggesting a possible competitive mechanism to release MITF for transcriptional activation. The mechanism depends precisely on the length of the phosphodiester linkage of Ap4A. These results highlight a direct polymerization signaling mechanism by the second messenger.