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

doi:10.1016/j.isci.2023.107199

Inositol polyphosphate multikinase modulates redox signaling through nuclear factor erythroid 2-related factor 2 and glutathione metabolism

iScience. 2023 Jun 24;26(7):107199. doi: 10.1016/j.isci.2023.107199. eCollection 2023 Jul 21.

Authors

Richa Tyagi¹, Suwarna Chakraborty², Sunil Jamuna Tripathi², Ik-Rak Jung³, Sangwon F Kim^{1

3}, Solomon H Snyder^{1

2

4}, Bindu D Paul^{1

2

4

5}

Affiliations

¹ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA.
⁴ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Lieber Institute for Brain Development, Baltimore, MD 21205, USA.

Abstract

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.

Keywords: Biological sciences; Cell biology; Molecular biology.

Abstract

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