Inositol polyphosphate multi‐kinase is a novel regulator of reverse‐transsulfuration pathway

Abstract

Inositol polyphosphate multikinase (IPMK) is one of the members of inositol phosphate kinase family that generates inositol polyphosphates. IPMK possesses inositol phosphate kinase (IP3‐kinase) as well as phosphatidylinositol kinase (PI3‐kinase) activities. IPMK is a pleiotropic protein and non‐catalytically regulates mammalian target of rapamycin complex 1 (mTORC1), serum response factor, p300, and tumor suppressor protein p53. We report that IPMK regulates expression of cystathionine γ‐lyase (CSE) and 3‐mercaptopyruvate sulfurtransferase (3‐MST), enzymes involved in Hydrogen sulfide production. Protein levels of CSE and MST are increased in IPMK null fibroblasts as compared to wild type fibroblast cells. Regulation of CSE and MST is independent of catalytic activity of IPMK. IPMK regulates CSE expression at the transcriptional level. Since cystathionine β‐synthase (CBS) is expressed at relatively lower levels as compare to CSE in fibroblasts, CSE is the major source of cysteine generation from cystathionine in mouse fibroblasts. Lysates prepared from IPMK null fibroblasts produced more cysteine as compared to wild type cells. Hydrogen sulfide levels are also increased in IPMK null fibroblasts. Expression of CSE is inducible upon condition such as lipopolysaccharides (LPS), and inflammation mediated by tumor necrosis factor α (TNF‐α). We propose that IPMK acts as a repressor of CSE expression.Support or Funding InformationThis work was supported by NIH grants MH18501 to S.H.S.