Inositol polyphosphate multikinase modulates redox signaling through nuclear factor erythroid 2-related factor 2 and glutathione metabolism
Richa Tyagi,
Suwarna Chakraborty,
Sunil Jamuna Tripathi,
Ik-Rak Jung,
Sangwon F. Kim,
Solomon H. Snyder,
Bindu D. Paul
Affiliations
Richa Tyagi
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Suwarna Chakraborty
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Sunil Jamuna Tripathi
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Ik-Rak Jung
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA
Sangwon F. Kim
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA
Solomon H. Snyder
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Bindu D. Paul
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Lieber Institute for Brain Development, Baltimore, MD 21205, USA; Corresponding author
Summary: Maintenance of redox balance plays central roles in a plethora of signaling processes. Although physiological levels of reactive oxygen and nitrogen species are crucial for functioning of certain signaling pathways, excessive production of free radicals and oxidants can damage cell components. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling cascade is the key pathway that mediates cellular response to oxidative stress. It is controlled at multiple levels, which serve to maintain redox homeostasis within cells. We show here that inositol polyphosphate multikinase (IPMK) is a modulator of Nrf2 signaling. IPMK binds Nrf2 and attenuates activation and expression of Nrf2 target genes. Furthermore, depletion of IPMK leads to elevated glutathione and cysteine levels, resulting in increased resistance to oxidants. Accordingly, targeting IPMK may restore redox balance under conditions of cysteine and glutathione insufficiency.
