The inositol phosphate signalling network in physiology and disease

Kim, Seyun; Bhandari, Rashna; Brearley, Charles A.; Saiardi, Adolfo

doi:10.1016/j.tibs.2024.08.005

Trends in Biochemical Sciences

2024

DOI: 10.1016/j.tibs.2024.08.005

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The inositol phosphate signalling network in physiology and disease

Seyun Kim,

Rashna Bhandari,

Charles A. Brearley

et al.

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2024

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Cited by 2 publications

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Functional Conservation of the DDP1-type Inositol Pyrophosphate Phosphohydrolases in Land Plant

Chalak,

Yadav,

Liu

et al. 2024

Biochemistry

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Inositol pyrophosphates (PP-InsPs) are eukaryote-specific second messengers that regulate diverse cellular processes, including immunity, nutrient sensing, and hormone signaling pathways in plants. These energy-rich messengers exhibit high sensitivity to the cellular phosphate status, suggesting that the synthesis and degradation of PP-InsPs are tightly controlled within the cells. Notably, the molecular basis of PP-InsP hydrolysis in plants remains largely unexplored. In this study, we report the functional characterization of MpDDP1, a diadenosine and diphosphoinositol polyphosphate phosphohydrolase encoded by the genome of the liverwort, Marchantia polymorpha. We show that MpDDP1 functions as a PP-InsP phosphohydrolase in different heterologous organisms. Consistent with this finding, M. polymorpha plants defective in MpDDP1 exhibit elevated levels of 1/3-InsP 7 and 1/3,5-InsP 8 , highlighting the contribution of MpDDP1 in regulating PP-InsP homeostasis in planta. Furthermore, our study reveals that MpDDP1 controls thallus development and vegetative reproduction in M. polymorpha. Collectively, this study provides insights into the regulation of specific PP-InsP messengers by DDP1-type phosphohydrolases in land plants.

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Functional Conservation of the DDP1-type Inositol Pyrophosphate Phosphohydrolases in Land Plant

Chalak,

Yadav,

Liu

et al. 2024

Biochemistry

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A non-catalytic role of IPMK is required for PLCγ1 activation in T cell receptor signaling by stabilizing the PLCγ1-Sam68 complex

Hong,

Kim,

Shim

et al. 2024

Cell Commun Signal

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Background Phospholipase C gamma 1 (PLCγ1) is an important mediator of the T cell receptor (TCR) and growth factor signaling. PLCγ1 is activated by Src family kinases (SFKs) and produces inositol 1,4,5-triphosphate (InsP 3 ) from phosphatidylinositol 4,5-bisphosphate (PIP 2 ). Inositol polyphosphate multikinase (IPMK) is a pleiotropic enzyme with broad substrate specificity and non-catalytic activities that mediate various functional protein-protein interactions. Therefore, IPMK plays critical functions in key biological events such as cell growth. However, the contribution of IPMK to the activation of PLCγ1 in TCR signaling remains mostly unelucidated. The current study aimed to elucidate the functions of IPMK in TCR signaling and to uncover the mode of IPMK-mediated signaling action in PLCγ1 activation. Methods Concanavalin A (ConA)-induced acute hepatitis model was established in CD4 + T cell-specific IPMK knockout mice (IPMK ΔCD4 ). Histological analysis was performed to assess hepatic injury. Primary cultures of naïve CD4 + T cells were used to uncover the role of mechanisms of IPMK in vitro. Western blot analysis, quantitative real-time PCR, and flow cytometry were performed to analyze the TCR-stimulation-induced PLCγ1 activation and the downstream signaling pathway in naïve CD4 + T cells. Yeast two-hybrid screening and co-immunoprecipitation were conducted to identify the IPMK-binding proteins and protein complexes. Results IPMK ΔCD4 mice showed alleviated ConA-induced acute hepatitis. CD4 + helper T cells in these mice showed reduced PLCγ1 Y783 phosphorylation, which subsequently dampens calcium signaling and IL-2 production. IPMK was found to contribute to PLCγ1 activation via the direct binding of IPMK to Src-associated substrate during mitosis of 68 kDa (Sam68). Mechanistically, IPMK stabilizes the interaction between Sam68 and to PLCγ1, thereby promoting PLCγ1 phosphorylation. Interfering this IPMK-Sam68 binding interaction with IPMK dominant-negative peptides impaired PLCγ1 phosphorylation. Conclusions Our results demonstrate that IPMK non-catalytically promotes PLCγ1 phosphorylation by stabilizing the PLCγ1–Sam68 complex. Targeting IPMK in CD4 + T cells may be a promising strategy for managing immune diseases caused by excessive stimulation of TCR. Supplementary Information The online version contains supplementary material available at 10.1186/s12964-024-01907-0.

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The inositol phosphate signalling network in physiology and disease

Cited by 2 publications

References 122 publications

Functional Conservation of the DDP1-type Inositol Pyrophosphate Phosphohydrolases in Land Plant

Functional Conservation of the DDP1-type Inositol Pyrophosphate Phosphohydrolases in Land Plant

A non-catalytic role of IPMK is required for PLCγ1 activation in T cell receptor signaling by stabilizing the PLCγ1-Sam68 complex

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