Inositol is an essential metabolite that plays a fundamental role in regulating cellular signaling pathways. In yeast, inositol affects the transcription of over 700 genes. In addition, many inositol phosphates and phosphoinositides are signaling molecules that control essential cellular pathways. Therefore, inositol homeostasis must be highly regulated. Numerous studies have shown that inositol biosynthesis is controlled at the level of transcription of the INO1 gene, which encodes myo-inositol 3-phosphate synthase (MIPS). However, regulation of inositol levels cannot be explained solely by modulating INO1 expression, as several physiological conditions that lead to inositol depletion are characterized by decreased inositol synthesis in spite of an increase in INO1 expression. In fact, preliminary studies indicate that decreased MIPS activity results from phosphorylation of the MIPS protein, not from decreased INO1 mRNA. Interestingly, inhibition of inositol synthesis perturbs vacuole function and V-ATPase activity. Based on these findings, the proposed study will address the hypothesis that inositol homeostasis is controlled by the phosphorylation of MIPS, and that inositol depletion leads to perturbation of vacuolar function and ATPase activity. The V-ATPase is a highly conserved pump that is essential for the transport of molecules into acidic organelles. In synaptic vesicles, V-ATPase activity drives the uptake of neurotransmitters. Therefore, perturbation of the V-ATPase by inositol depleting drugs is expected to have important implications for neurotransmission.
The specific aims will address the following questions: 1) What is the mechanism underlying the phosphorylation of MIPS? 2) How does inositol depletion lead to perturbation of vacuolar function? 3) What mechanisms control MIPS in human cells? This study will characterize for the first time a novel regulatory mechanism that controls inositol homeostasis and that links this regulation to vacuolar function and V-ATPase activity. This study will also address the serious gap in our understanding of how inositol synthesis is regulated in human cells. Because inositol-containing compounds are involved in disorders as diverse as neurological and psychiatric illnesses, myopathies, cancer, and diabetes, the outcome of these studies will have a powerful impact on understanding regulatory pathways crucial to human health.
The proposed study will elucidate a novel molecular mechanism of control of inositol homeostasis and the cellular consequences of this regulation. Inositol is an essential metabolic sensor that plays a fundamental role in regulating cellular signaling pathways. Because inositol-containing compounds are involved in disorders as diverse as neurological and psychiatric illnesses, myopathies, cancer, and diabetes, the outcome of these studies will have a powerful impact on understanding regulatory pathways crucial to human health.
|Jadhav, Shyamalagauri; Russo, Sarah; Cowart, L Ashley et al. (2017) Inositol Depletion Induced by Acute Treatment of the Bipolar Disorder Drug Valproate Increases Levels of Phytosphingosine. J Biol Chem 292:4953-4959|
|Yu, Wenxi; Daniel, Joshua; Mehta, Dhara et al. (2017) MCK1 is a novel regulator of myo-inositol phosphate synthase (MIPS) that is required for inhibition of inositol synthesis by the mood stabilizer valproate. PLoS One 12:e0182534|
|Yu, Wenxi; Ye, Cunqi; Greenberg, Miriam L (2016) Inositol Hexakisphosphate Kinase 1 (IP6K1) Regulates Inositol Synthesis in Mammalian Cells. J Biol Chem 291:10437-44|
|Jadhav, Shyamalagauri; Russo, Sarah; Cottier, Stéphanie et al. (2016) Valproate Induces the Unfolded Protein Response by Increasing Ceramide Levels. J Biol Chem 291:22253-22261|
|Yu, Wenxi; Greenberg, Miriam L (2016) Inositol depletion, GSK3 inhibition and bipolar disorder. Future Neurol 11:135-148|
|Ye, Cunqi; Greenberg, Miriam L (2015) Inositol synthesis regulates the activation of GSK-3? in neuronal cells. J Neurochem 133:273-83|
|Deranieh, Rania M; Shi, Yihui; Tarsio, Maureen et al. (2015) Perturbation of the Vacuolar ATPase: A NOVEL CONSEQUENCE OF INOSITOL DEPLETION. J Biol Chem 290:27460-72|
|Jadhav, Shyamalagauri; Greenberg, Miriam L (2014) Harnessing the power of yeast to elucidate the role of sphingolipids in metabolic and signaling processes pertinent to psychiatric disorders. Clin Lipidol 9:533-551|
|Deranieh, Rania M; He, Quan; Caruso, Joseph A et al. (2013) Phosphorylation regulates myo-inositol-3-phosphate synthase: a novel regulatory mechanism of inositol biosynthesis. J Biol Chem 288:26822-33|
|Ye, Cunqi; Bandara, W M M S; Greenberg, Miriam L (2013) Regulation of inositol metabolism is fine-tuned by inositol pyrophosphates in Saccharomyces cerevisiae. J Biol Chem 288:24898-908|
Showing the most recent 10 out of 14 publications