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; Jing Wang

doi:10.1038/s41467-019-12710-8

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, Jing Wang^*

^*Corresponding author for this work

Institute for Medical Research Israel-Canada (IMRIC)

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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.

Original language	English
Article number	4664
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12710-8
State	Published - 1 Dec 2019

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Publisher Copyright:
© 2019, The Author(s).

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10.1038/s41467-019-12710-8

Cite this

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

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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AU - Yu, Jing

AU - Liu, Zaizhou

AU - Liang, Yuanyuan

AU - Luo, Feng

AU - Zhang, Jie

AU - Tian, Cuiping

AU - Motzik, Alex

AU - Zheng, Mengmeng

AU - Kang, Jingwu

AU - Zhong, Guisheng

AU - Liu, Cong

AU - Fang, Pengfei

AU - Guo, Min

AU - Razin, Ehud

AU - Wang, Jing

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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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