Nat Metab Rao Feng/Dynasty's team discovered a new messenger in the GPCR pathway that regulates vesicle secretion and metabolic homeostasis: IP7

Editor | Xi Diabetes is usually accompanied by abnormal insulin levels
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Therefore, the strict regulation of insulin secretion has important physiological and pathological significance for the body to maintain glucose homeostasis
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Insulin secretion in beta cells in the body is strictly regulated by glucose, hormones, neurotransmitters, etc.
The parasympathetic nerve stimulation of insulin secretion is one of the important mechanisms
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The signaling pathways through which parasympathetic signals are sensed in β cells and how they stimulate the release of insulin vesicles are not entirely clear
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Advanced inositol polyphosphate is derived from the GPCR messenger IP3, a small metabolic molecule formed by a series of hierarchical phosphorylation of inositol kinases.
It is evolutionarily conserved but its function is poorly understood (Figure 1)
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Rao Feng's research group from the School of Life Sciences of Southern University of Science and Technology is mainly studying the functional mechanism of emerging small molecule messengers in cells represented by high-grade inositol polyphosphate
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It has been found that inositol hexaphosphate (IP6) is an intermolecular "glue" that promotes the assembly of the CSN-CRL ubiquitin ligase regulatory complex (see BioArt report: Rao Feng/Wang Tao's group reveals that metabolic small molecules regulate CRL ubiquitin ligase The function and mechanism of mimicking modification) [1]; also by characterizing CSN2-K70E mutant mice lacking IP6 binding, a protein degradation pathway was discovered that senses glucose to stimulate insulin secretion (see BioArt report: Nat CommunRao The Feng group discovered that the CSN-CRL4COP1-ETV5 protein degradation pathway that senses glucose stimulates insulin secretion and its association with hyperinsulinemia) [2]
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Inositol pyrophosphate 5-IP7 (IP7) is produced by phosphorylating IP6 by its synthetic kinase IP6K
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IP7 has high energy, and is dynamically converted with IP6 under the action of IP6K and phosphatase (DIPP), and has the properties of instantaneous synthesis and degradation of messenger molecules
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According to the phenotype of IP6K knockout mice and cell lines, IP7 should be involved in many physiological and disease processes, such as regulating the fate of tumor cell apoptosis and metastasis [3,4]
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However, the universal action principle of IP7 and the physiological signal pathways transduced by it are still unclear
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Figure 1: Research on the messenger function and mechanism of advanced poly-inositol metabolism molecules
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IP6K-mediated dynamic conversion between IP6-IP7 may be involved in the response of cells to external signals/stimulus/stress
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However, the signals involved in the response of IP6K and the target and mechanism of action of IP7 are unknown
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On October 18, 2021, Rao Feng's research group from the School of Life Sciences of Southern University of Science and Technology and Wang Chao's research group of the Department of Life Sciences and Medicine of the University of Science and Technology of China jointly published the title: 5-IP7 is a GPCR messenger mediating neural control in Nature Metabolism.
of synaptotagmin-dependent insulin exocytosis and glucose homeostasis
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Reported a new GPCR messenger: IP7, and its function and molecular mechanism of inducing parasympathetic nerve signals to stimulate insulin secretion
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In this study, the author first analyzed the phosphorylation activation regulation mechanism of IP6K1 under physiological conditions.
When the parasympathetic nerve is activated, the acetylcholine receptors distributed on the surface of the pancreatic islet β cells receive acetylcholine from the nerve endings through a series of signals.
The transduction process (Ach-M3R-Gαq/11-PLC-PKC/PKD-IP6K1) phosphorylates IP6K1 and promotes the production of IP7 (Figure 2A)
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Furthermore, the authors constructed simulated phosphorylation-modified IP6K1 S118/121D mutant mice and β-cell IP6K1 specific knockout IP6K1fl/fl:MIP-Cre mice, and characterized their related metabolic indicators, and found that the parasympathetic nerve stimulates pancreatic β-cells The generated IP7 can further promote insulin secretion and glucose homeostasis regulation
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For example, it is found that IP6K1 S118/121D mice have higher serum insulin levels, better glucose tolerance, and its islets also have stronger insulin secretion ability
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In contrast, IP6K1fl/fl:MIP-Cre mice showed impaired glucose-induced insulin secretion and worse glucose tolerance
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From this, the authors concluded that IP6K1, after being activated by the parasympathetic transmitter acetylcholine receptor, can promote insulin secretion through its enzymatic product 5-IP7
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This is the first report on the physiological regulation of IP6K enzyme activity and a new discovery in the periphery of central regulation
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Figure 2: The acetylcholine receptor-Gq-PLC-PKC signaling pathway modifies the phosphorylation of IP6K1 and the physiological background involved in neuroregulation and metabolism
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In order to further analyze the mechanism by which IP7 promotes insulin secretion, the authors systematically characterized the number, size and insulin content of islets and the degree of docking with vesicles, and found that IP7 does not participate in these processes
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By analyzing the crystal structure of the insulin secretion-related synaptic binding protein Syt7 and phosphoinositide complex, the authors found that IP7 can compete with PIP2 to bind to Syt7, thereby inhibiting spontaneous vesicle release without stimulation
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In the process of fusion of insulin vesicles and cell membranes stimulated by calcium influx, calcium ions can bind to 5-IP7, which promotes the binding of Syt7 to PIP2 on the cell membrane, and promotes the natural fusion of SNARE-mediated vesicles with the cell membrane
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IP6, the precursor of IP7, has a weaker binding capacity to calcium ions.
This difference is amplified when IP6K1 is activated or in the S118/121D mutant of IP6K1, resulting in higher than normal levels of mouse insulin secretion (Figure 3)
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Based on this, the author proposes that when the Gq-coupled GPCR is activated, IP7 is a "coincident messenger" that interacts with Ca2+ to participate in the release of vesicles
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Figure 3: 5-IP7 and Ca2+ act as a "coincident messenger" downstream of the GPCR pathway of the acetylcholine receptor to stimulate the release of insulin vesicles
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This work found for the first time that IP7 is the second messenger of Gq-coupled GPCR, and is similar to the famous messenger molecule cAMP (Note: cAMP is the second messenger of Gs-coupled GPCR)
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The more extensive and important messenger function of the metabolic small molecule IP7 needs to be further explored
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Zhang Xiaozhe, PhD student in Rao Feng's research group of Southern University of Science and Technology, PhD student Li Na, master's student Zhang Jun, Zhang Yanshen, PhD student in Wang Chao's research group of University of Science and Technology of China, and Yang Xiaoli, research assistant of Rao Feng's research group are the co-first authors of this paper
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Professor Rao Feng and Professor Wang Chao are the co-corresponding authors of this article
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Original link: https:// Rao Feng's research group recruitment notice Rao Feng's research group plans to recruit a total of 2-3 research assistants or post-doctoral fellows.
This recruitment advertisement is longer Effective within the time limit until the right talent is hired
.

Introduction to the research group: Rao Feng, researcher and doctoral supervisor of the School of Life Sciences, Southern University of Science and Technology
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Mainly research messenger and metabolic biology, comprehensively explore the functional mechanism of emerging small molecular messengers in the cell and the metabolic regulation of protein homeostasis from the three levels of molecules, cells and mouse models, and how these life processes in the disease microenvironment participate in nerves Intermodulation and interaction with metabolism and tumor tissue
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The foundation for the research topics to be launched by the recruited talents has been prepared, and the focus will be on the GPCR messenger function of inositol pyrophosphate, and protein homeostasis reprogramming triggered by nutrient perception
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After the establishment of the laboratory, he published several corresponding author papers in Nat Metab (2021), Nat Commun (2021), PNAS (2020, 2016) and JBC (2020), and was awarded as Outstanding Youth of the National Foundation of China (2021), Shenzhen Peacock Plan the team (2021) and other projects
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The research fund of the research group is sufficient
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The remuneration is generous and implemented in accordance with the Shenzhen standard.
Those with outstanding performance can apply for research assistant professors, etc.
to assist in the settlement of their children's enrollment in kindergartens
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For details, please refer to the research team homepage: http://faculty.
sustech.
edu.
cn/raof/ Recruitment notice of the Dynasty Research Group The Dynasty Research Group plans to recruit 2-3 special-appointed associate researchers or post-doctoral fellows.
This recruitment advertisement will take a long time.
Effective within, until the right talent is hired
.

Introduction to the research group: Wang Chao, professor and doctoral supervisor of the Department of Life Sciences and Medicine, University of Science and Technology of China
.

The main research direction is neurostructural chemical biology.
Through the systematic study of the structure, function and chemical biological regulation of protein complexes mediated by important scaffold proteins in the nervous system, to deeply understand the establishment and maintenance of nerve cell polarity, as well as nerves.
The molecular mechanism of network loop regulation
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The recruitment will be to expand the research topic has prepared foundation, research will focus on the organizational structure of the axon initial segment, identify protein interaction networks and groups
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After setting up the laboratory, he published several corresponding author papers in Nat Metab (2021), Nat Chem Biol (2018), Nat Commun (2021), PNAS (2020, 2021) and other journals, and won the National Foundation Excellent Youth Project (2021), Hundred Chinese Academy of Sciences (2016), USTC academic leading talent (2021) and so on
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The research fund of the research group is sufficient
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The benefits are implemented in accordance with the relevant management regulations of the University of Science and Technology of China, and those with outstanding performance can apply for special funding, etc.
, to solve the problem of children's enrollment in kindergartens (the best kindergartens, primary and secondary schools in Anhui Province)
.

Resume delivery (if you are interested, please send your resume and other materials to): https://jinshuju.
net/f/ZqXwZt or scan the QR code to deliver your resume.
Platemaker: 11 References 1 Lin, H.
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et al.
IP6-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion.
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1038/s41467-021-22941-3 (2021).
3 Rao, F.
et al.
Inositol pyrophosphates mediate the DNA -PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2.
Mol Cell 54, 119-132, doi:10.
1016/j.
molcel.
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4 Rao, F.
et al.
Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1.
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1424642112 (2015).
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