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

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

doi:10.1038/s41467-019-12710-8

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

Journal Article · Fri Oct 11 00:00:00 EDT 2019 · Nature Communications

DOI:https://doi.org/10.1038/s41467-019-12710-8· OSTI ID:1574165

Yu, Jing ^[1]; Liu, Zaizhou ^[1]; Liang, Yuanyuan ^[1]; Luo, Feng ^[2]; Zhang, Jie ^[1]; Tian, Cuiping ^[3]; Motzik, Alex ^[4]; Zheng, Mengmeng ^[1]; Kang, Jingwu ^[1]; Zhong, Guisheng ^[3];

^[2];

^[1]; Guo, Min ^[5]; Razin, Ehud ^[6];

^[1]

Univ. of Chinese Academy of Sciences, Shanghai (China). State Key Lab. of Bioorganic and Natural Products Chemistry
Chinese Academy of Sciences (CAS), Shanghai (China). Interdisciplinary Research Center on Biology and Chemistry
ShanghaiTech Univ. (China). iHuman Inst.
Hebrew Univ. Medical School, Jerusalem (Israel)
Univ. of Chinese Academy of Sciences, Shanghai (China). State Key Lab. of Bioorganic and Natural Products Chemistry; Kangma BioTech Co. Ltd., Shanghai (China)
Hebrew Univ. Medical School, Jerusalem (Israel); National Univ. of Singapore (Singapore). NUS-HUJ-Create Cellular and Molecular Mechanisms of Inflammation Program

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 Ap_{4A 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.}

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Chinese Academy of Sciences (CAS); National Natural Science Foundation of China (NSFC); National Institutes of Health (NIH); Israel Science Foundation; Hebrew-University-National Research Foundation of Singapore

Grant/Contract Number:: XDB20000000; 21778067; 21977108; 21778064; 21977107; GM100136; GM106134; 115/2013; R182-005-172-281

OSTI ID:: 1574165

Journal Information:: Nature Communications, Vol. 10, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 8 works

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