Photolysis of cell-permeant caged inositol pyrophosphates controls oscillations of cytosolic calcium in a β-cell line

Hauke, Sebastian; Dutta, Amit K.; Eisenbeis, Verena B.; Bezold, Dominik; Bittner, Tamara; Wittwer, Christopher; Thakor, Divyeshsinh T.; Pavlovic, Igor; Schultz, Carsten; Jessen, Henning J.

doi:10.1039/c8sc03479f

Cited by 21 publications

(31 citation statements)

References 37 publications

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“…To confirm that BCR signaling requires higher order InsPs, we tested if cell permeable InsP could rescue the impairment in activation of IPMK-deficient B cells. Fo B cells and MZ B cells isolated from IPMK cKO mice were activated in the presence of cell permeable InsP 5 or InsP 6 (39)(40)(41), and then the phosphorylation of Btk and PLCγ2 was measured. The treatment with cell permeable InsP 6 only resulted in substantial restoration of phosphorylation of both Btk and PLCγ2 after stimulation with anti-IgM ( Fig.…”

Section: Ipmk Deficiency Impairs B Cell Proliferation During a Responmentioning

confidence: 99%

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

Kim

Min

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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T cell-independent (TI) B cell response is critical for the early protection against pathogen invasion. The regulation and activation of Bruton’s tyrosine kinase (Btk) is known as a pivotal step of B cell antigen receptor (BCR) signaling in TI humoral immunity, as observed in patients with X-linked agammaglobulinemia (XLA) experiencing a high incidence of encapsulated bacterial infections. However, key questions remain as to whether a well-established canonical BCR signaling pathway is sufficient to regulate the activity of Btk. Here, we find that inositol hexakisphosphate (InsP6) acts as a physiological regulator of Btk in BCR signaling. Absence of higher order inositol phosphates (InsPs), inositol polyphosphates, leads to an inability to mount immune response against TI antigens. Interestingly, the significance of InsP6-mediated Btk regulation is more prominent in IgM+plasma cells. Hence, the present study identifies higher order InsPs as principal components of B cell activation upon TI antigen stimulation and presents a mechanism for InsP-mediated regulation of the BCR signaling.

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Section: Ipmk Deficiency Impairs B Cell Proliferation During a Responmentioning

confidence: 99%

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

Kim

Min

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…To obtain direct evidence that 5-InsP 7 mediates Na + /K + -ATPase-1 endocytosis, we overexpressed green fluorescent protein (GFP)-fused Na + /K + -ATPase-1 in HEK 293 cells, and treated the cells with cell-permeant photocaged 5-InsP 7 ( fig. S6C) (22) to observe its influence upon GFP-fused Na + /K + -ATPase-1 in real time via confocal microscopy ( Fig. 3G).…”

Section: -Insp 7 Promotes Na + /K + -Atpase-1 Endocytosismentioning

confidence: 99%

The inositol pyrophosphate 5-InsP ₇ drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α

et al. 2020

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Sodium/potassium-transporting adenosine triphosphatase (Na+/K+-ATPase) is one of the most abundant cell membrane proteins and is essential for eukaryotes. Endogenous negative regulators have long been postulated to play an important role in regulating the activity and stability of Na+/K+-ATPase, but characterization of these regulators has been elusive. Mechanisms of regulating Na+/K+-ATPase homeostatic turnover are unknown. Here, we report that 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP7), generated by inositol hexakisphosphate kinase 1 (IP6K1), promotes physiological endocytosis and downstream degradation of Na+/K+-ATPase-α1. Deletion of IP6K1 elicits a twofold enrichment of Na+/K+-ATPase-α1 in plasma membranes of multiple tissues and cell types. Using a suite of synthetic chemical biology tools, we found that 5-InsP7 binds the RhoGAP domain of phosphatidylinositol 3-kinase (PI3K) p85α to disinhibit its interaction with Na+/K+-ATPase-α1. This recruits adaptor protein 2 (AP2) and triggers the clathrin-mediated endocytosis of Na+/K+-ATPase-α1. Our study identifies 5-InsP7 as an endogenous negative regulator of Na+/K+-ATPase-α1.

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“…The resultant, uncharged molecule can penetrate the plasma membrane, and once it is inside cells, intracellular esterases cleave the masking groups and yielded the native inositol phosphate. This technique has been adapted by Jessen and colleagues [ 69 ], such that caged 5-InsP 7 was made cell-permeable by attaching acetoxybenzyl groups to the monophosphates and DEACM was added to the 5-β-phosphate ( Figure 4 B). Cell loading and removal of the acetoxybenzyl moieties was completed within 4 hr.…”

Section: Caged and Cell-permeant Pp-inspsmentioning

confidence: 99%

Metabolism and Functions of Inositol Pyrophosphates: Insights Gained from the Application of Synthetic Analogues

Shears

Wang

2020

Molecules

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Inositol pyrophosphates (PP-InsPs) comprise an important group of intracellular, diffusible cellular signals that a wide range of biological processes throughout the yeast, plant, and animal kingdoms. It has been difficult to gain a molecular-level mechanistic understanding of the actions of these molecules, due to their highly phosphorylated nature, their low levels, and their rapid metabolic turnover. More recently, these obstacles to success are being surmounted by the chemical synthesis of a number of insightful PP-InsP analogs. This review will describe these analogs and will indicate the important chemical and biological information gained by using them.

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Photolysis of cell-permeant caged inositol pyrophosphates controls oscillations of cytosolic calcium in a β-cell line

Abstract: β-Cells respond directly to the intracellular photochemical release of caged inositol pyrophosphate isomers with modulations of oscillations in cytosolic Ca2+.

Cited by 21 publications

References 37 publications

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

The inositol pyrophosphate 5-InsP ₇ drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α

Metabolism and Functions of Inositol Pyrophosphates: Insights Gained from the Application of Synthetic Analogues

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Photolysis of cell-permeant caged inositol pyrophosphates controls oscillations of cytosolic calcium in a β-cell line

Abstract: β-Cells respond directly to the intracellular photochemical release of caged inositol pyrophosphate isomers with modulations of oscillations in cytosolic Ca2+.

Cited by 21 publications

References 37 publications

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

The inositol pyrophosphate 5-InsP 7 drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α

Metabolism and Functions of Inositol Pyrophosphates: Insights Gained from the Application of Synthetic Analogues

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The inositol pyrophosphate 5-InsP ₇ drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α