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Phosphatidylinositol 4-kinase IIIβ mediates contraction-induced GLUT4 translocation and shows its anti-diabetic action in cardiomyocytes.

ABSTRACT: In the diabetic heart, long-chain fatty acid (LCFA) uptake is increased at the expense of glucose uptake. This metabolic shift ultimately leads to insulin resistance and a reduced cardiac function. Therefore, signaling kinases that mediate glucose uptake without simultaneously stimulating LCFA uptake could be considered attractive anti-diabetic targets. Phosphatidylinositol-4-kinase-IIIβ (PI4KIIIβ) is a lipid kinase downstream of protein kinase D1 (PKD1) that mediates Golgi-to-plasma membrane vesicular trafficking in HeLa-cells. In this study, we evaluated whether PI4KIIIβ is involved in myocellular GLUT4 translocation induced by contraction or oligomycin (an F₁F₀-ATP synthase inhibitor that activates contraction-like signaling). Pharmacological targeting, with compound MI14, or genetic silencing of PI4KIIIβ inhibited contraction/oligomycin-stimulated GLUT4 translocation and glucose uptake in cardiomyocytes but did not affect CD36 translocation nor LCFA uptake. Addition of the PI4KIIIβ enzymatic reaction product phosphatidylinositol-4-phosphate restored oligomycin-stimulated glucose uptake in the presence of MI14. PI4KIIIβ activation by PKD1 involves Ser294 phosphorylation and altered its localization with unchanged enzymatic activity. Adenoviral PI4KIIIβ overexpression stimulated glucose uptake, but did not activate hypertrophic signaling, indicating that unlike PKD1, PI4KIIIβ is selectively involved in GLUT4 translocation. Finally, PI4KIIIβ overexpression prevented insulin resistance and contractile dysfunction in lipid-overexposed cardiomyocytes. Together, our studies identify PI4KIIIβ as positive and selective regulator of GLUT4 translocation in response to contraction-like signaling, suggesting PI4KIIIβ as a promising target to rescue defective glucose uptake in diabetics.

SUBMITTER: Sun A

PROVIDER: S-EPMC8004495 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Enteroviruses are one of the most abundant viruses causing mild to serious acute infections in humans and also contributing to chronic diseases like type 1 diabetes. Presently, there are no approved antiviral drugs against enteroviruses. Here, we studied the potency of vemurafenib, an FDA-approved RAF kinase inhibitor for treating BRAFV600E mutant-related melanoma, as an antiviral against enteroviruses. We showed that vemurafenib prevented enterovirus translation and replication at low micromolar dosage in an RAF/MEK/ERK-independent manner. Vemurafenib was effective against group A, B, and C enteroviruses, as well as rhinovirus, but not parechovirus or more remote viruses such as Semliki Forest virus, adenovirus, and respiratory syncytial virus. The inhibitory effect was related to a cellular phosphatidylinositol 4-kinase type IIIβ (PI4KB), which has been shown to be important in the formation of enteroviral replication organelles. Vemurafenib prevented infection efficiently in acute cell models, eradicated infection in a chronic cell model, and lowered virus amounts in pancreas and heart in an acute mouse model. Altogether, instead of acting through the RAF/MEK/ERK pathway, vemurafenib affects the cellular PI4KB and, hence, enterovirus replication, opening new possibilities to evaluate further the potential of vemurafenib as a repurposed drug in clinical care. IMPORTANCE Despite the prevalence and medical threat of enteroviruses, presently, there are no antivirals against them. Here, we show that vemurafenib, an FDA-approved RAF kinase inhibitor for treating BRAFV600E mutant-related melanoma, prevents enterovirus translation and replication. Vemurafenib shows efficacy against group A, B, and C enteroviruses, as well as rhinovirus, but not parechovirus or more remote viruses such as Semliki Forest virus, adenovirus, and respiratory syncytial virus. The inhibitory effect acts through cellular phosphatidylinositol 4-kinase type IIIβ (PI4KB), which has been shown to be important in the formation of enteroviral replication organelles. Vemurafenib prevents infection efficiently in acute cell models, eradicates infection in a chronic cell model, and lowers virus amounts in pancreas and heart in an acute mouse model. Our findings open new possibilities to develop drugs against enteroviruses and give hope for repurposing vemurafenib as an antiviral drug against enteroviruses.

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Phosphatidylinositol 4-kinase IIIβ mediates contraction-induced GLUT4 translocation and shows its anti-diabetic action in cardiomyocytes.

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