Second messenger Ap4A polymerizes target protein HINT1 to transduce signals in FcεRI-activated mast cells

Jing Yu, Zaizhou Liu, Yuanyuan Liang, Feng Luo, Jie Zhang, Cuiping Tian, Alex Motzik, Mengmeng Zheng, Jingwu Kang, Guisheng Zhong, Cong Liu, Pengfei Fang, Min Guo, Ehud Razin () and Jing Wang ()
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Jing Yu: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Zaizhou Liu: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yuanyuan Liang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Feng Luo: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Jie Zhang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Cuiping Tian: ShanghaiTech University
Alex Motzik: Institute for Medical Research Israel-Canada, Hebrew University Medical School
Mengmeng Zheng: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Jingwu Kang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Guisheng Zhong: ShanghaiTech University
Cong Liu: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Pengfei Fang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Min Guo: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Ehud Razin: Institute for Medical Research Israel-Canada, Hebrew University Medical School
Jing Wang: University of Chinese Academy of Sciences, Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12710-8

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