Inositol hexakisphosphate increases the size of platelet aggregates

Brehm, Maria A.; Klemm, Ulrike; Rehbach, Christoph; Erdmann, Nina; Kolšek, Katra; Lin, Hongying; Aponte-Santamaría, Camilo; Gräter, Frauke; Rauch, Bernhard; Riley, Andrew M.; Mayr, Georg W.; Potter, Barry V. L.; Windhorst, Sabine

doi:10.1016/j.bcp.2018.12.011

Cited by 9 publications

(9 citation statements)

References 47 publications

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“…These highly charged small molecules include inositol-1,3,4,5,6-pentakisphosphate (IP5) and IP6. IP6 binds to numerous host cell proteins and regulates diverse biological processes, including chromatin remodeling ( 11 ), mRNA nuclear export ( 12 , 13 ), platelet aggregation ( 14 ), prion propagation ( 15 ), and circadian rhythm ( 16 ). IP6 also binds to the HIV-1 capsid in vitro and stabilizes the hexameric CA lattice.…”

Section: Introductionmentioning

confidence: 99%

The Host Cell Metabolite Inositol Hexakisphosphate Promotes Efficient Endogenous HIV-1 Reverse Transcription by Stabilizing the Viral Capsid

Jennings

Shi

Varadarajan

et al. 2020

mBio

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A defining activity of retroviruses is reverse transcription, the process by which the viral genomic RNA is converted into the double-stranded DNA required for virus replication. Reverse transcriptase (RT), the viral enzyme responsible for this process, was identified in 1970 by assaying permeabilized retrovirus particles for DNA synthesis in vitro. Such reactions are inefficient, with only a small fraction of viral genomes being converted to full-length double-stranded DNA molecules, possibly owing to disruption of the structure of the viral core. Here, we show that reverse transcription in purified HIV-1 cores is enhanced by the addition of the capsid-binding host cell metabolite inositol hexakisphosphate (IP6). IP6 potently enhanced full-length minus-strand synthesis, as did hexacarboxybenzene (HCB), which also stabilizes the HIV-1 capsid. Both IP6 and HCB stabilized the association of the viral CA and RT proteins with HIV-1 cores. In contrast to the wild type, cores isolated from mutant HIV-1 particles containing intrinsically hyperstable capsids exhibited relatively efficient reverse transcription in the absence of IP6, further indicating that the compound promotes reverse transcription by stabilizing the viral capsid. We also observed that the capsid-destabilizing antiviral compound PF74 inhibited endogenous reverse transcription with a potency that mirrors its ability to inhibit reverse transcription during infection. Our results show that the stabilization of the HIV-1 capsid permits efficient reverse transcription in HIV-1 cores, providing a sensitive experimental system for analyzing the functions of viral and host cell molecules and the role of capsid disassembly (uncoating) in the process. IMPORTANCE HIV-1 infection requires reverse transcription of the viral genome. While much is known about the biochemistry of reverse transcription from simplified biochemical reactions, reverse transcription during infection takes place within a viral core. However, endogenous reverse transcription reactions using permeabilized HIV-1 virions or purified viral cores have been inefficient. Using viral cores purified from infectious HIV-1 particles, we show that efficient reverse transcription is achieved in vitro by addition of the capsid-stabilizing metabolite inositol hexakisphosphate. The enhancement of reverse transcription was linked to the capsid-stabilizing effect of the compound, consistent with the known requirement for an intact or semi-intact viral capsid for HIV-1 infection. Our results establish a biologically relevant system for dissecting the function of the viral capsid and its disassembly during reverse transcription. The system should also prove useful for mechanistic studies of capsid-targeting antiviral drugs.

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Section: Introductionmentioning

confidence: 99%

The Host Cell Metabolite Inositol Hexakisphosphate Promotes Efficient Endogenous HIV-1 Reverse Transcription by Stabilizing the Viral Capsid

Jennings

Shi

Varadarajan

et al. 2020

mBio

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“…However, a recent report that IP6 can increase platelet aggregate size [ 89 ] needs to be addressed. Additionally, it appears that platelets have ability to interact with tumor cells in the circulation, contributing to the “circulome” formation [ 90 ].…”

Section: Discussionmentioning

confidence: 99%

Inositol Hexaphosphate (IP6) and Colon Cancer: From Concepts and First Experiments to Clinical Application

Vučenik

Družijanić

2020

Molecules

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Multiple human health-beneficial effects have been related to highly phosphorylated inositol hexaphosphate (IP6). This naturally occurring carbohydrate and its parent compound, myo-inositol (Ins), are abundantly present in plants, particularly in certain high-fiber diets, but also in mammalian cells, where they regulate important cellular functions. However, the striking and broad-spectrum anticancer activity of IP6, consistently demonstrated in different experimental models, has been in a spotlight of the scientific community dealing with the nutrition and cancer during the last several decades. First experiments were performed in colon cancer 30 years ago. Since then, it has been shown that IP6 reduces cell proliferation, induces apoptosis and differentiation of malignant cells with reversion to normal phenotype, affecting several critical molecular targets. Enhanced immunity and antioxidant properties also contribute to the tumor cell destruction. Although Ins possesses a modest anticancer potential, the best anticancer results were obtained from the combination of IP6 + Ins. Here we review the first experimental steps in colon cancer, when concepts and hypotheses were put together almost without real knowledge and present clinical studies, that were initiated in colon cancer patients. Available as a dietary supplement, IP6 + Ins has been shown to enhance the anticancer effect of conventional chemotherapy, controls cancer metastases, and improves quality of life in cancer patients. Emerging clinical and still vast amount of experimental data suggest its role either as an adjuvant or as an “alternative” to current chemotherapy for cancer.

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“…Importantly, this study has revealed a role for Ins P 6 in regulation of platelet aggregate size, in a mechanism involving its interaction with fibrinogen. Although previous evidence identified both Ins P 5 and Ins P 6 as binding partners of fibrinogen [ 47 ], InsP 5 did not have a role in regulation of aggregation, which appeared specific for InsP 6 [ 46 ]. The authors suggested a role for Ins P 6 in supporting and stabilizing the crosslinking between fibrinogen and platelets, identifying this IP as a novel potential player in regulation of platelet functions [ 46 ].…”

Section: Intracellular Processes Regulated By Ips Binding To Protementioning

confidence: 94%

“…A recent study has reported the increase of Ins P 6 in platelets upon stimulation with thrombin, collagen I and ADP [ 46 ]. Importantly, this study has revealed a role for Ins P 6 in regulation of platelet aggregate size, in a mechanism involving its interaction with fibrinogen.…”

Section: Intracellular Processes Regulated By Ips Binding To Protementioning

confidence: 99%

Signalling Properties of Inositol Polyphosphates

Maffucci

Falasca

2020

Molecules

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Several studies have identified specific signalling functions for inositol polyphosphates (IPs) in different cell types and have led to the accumulation of new information regarding their cellular roles as well as new insights into their cellular production. These studies have revealed that interaction of IPs with several proteins is critical for stabilization of protein complexes and for modulation of enzymatic activity. This has not only revealed their importance in regulation of several cellular processes but it has also highlighted the possibility of new pharmacological interventions in multiple diseases, including cancer. In this review, we describe some of the intracellular roles of IPs and we discuss the pharmacological opportunities that modulation of IPs levels can provide.

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Inositol hexakisphosphate increases the size of platelet aggregates

Abstract: Graphical abstract

Cited by 9 publications

References 47 publications

The Host Cell Metabolite Inositol Hexakisphosphate Promotes Efficient Endogenous HIV-1 Reverse Transcription by Stabilizing the Viral Capsid

The Host Cell Metabolite Inositol Hexakisphosphate Promotes Efficient Endogenous HIV-1 Reverse Transcription by Stabilizing the Viral Capsid

Inositol Hexaphosphate (IP6) and Colon Cancer: From Concepts and First Experiments to Clinical Application

Signalling Properties of Inositol Polyphosphates

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