2. Academic Validation
  3. Second messenger Ap4A polymerizes target protein HINT1 to transduce signals in FcεRI-activated mast cells

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

  • Nat Commun. 2019 Oct 11;10(1):4664. doi: 10.1038/s41467-019-12710-8.
Jing Yu 1,  Zaizhou Liu 1,  Yuanyuan Liang 1,  Feng Luo 2,  Jie Zhang 1,  Cuiping Tian 3,  Alex Motzik 4,  Mengmeng Zheng 1,  Jingwu Kang 1,  Guisheng Zhong 3,  Cong Liu 2,  Pengfei Fang 1,  Min Guo 1 5,  Ehud Razin 6 7,  Jing Wang 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
  • 2 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
  • 3 iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
  • 4 Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, 91120, Israel.
  • 5 Kangma BioTech, Co., Ltd, 1131 Cailun Road, Shanghai, 201203, China.
  • 6 Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, 91120, Israel. ehudr@ekmd.huji.ac.il.
  • 7 NUS-HUJ-CREATE Cellular and Molecular Mechanisms of Inflammation Program, Department of Microbiology and Immunology, National University of Singapore, Singapore, 117597, Singapore. ehudr@ekmd.huji.ac.il.
  • 8 State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Jwang@sioc.ac.cn.
PMID: 31604935 DOI: 10.1038/s41467-019-12710-8
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.

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