InsP <sub>7</sub> is a small-molecule regulator of NUDT3-mediated mRNA decapping and processing-body dynamics
Soumyadip Sahu, Zhenzhen Wang, Xinfu Jiao, Chunfang Gu, Nikolaus Jork, Christopher Wittwer, Xingyao Li, Sarah Hostachy, Dorothea Fiedler, Huanchen Wang, Henning J. Jessen, Megerditch Kiledjian, Stephen B. Shears
Abstract
Significance Improved understanding of the epitranscriptomic control process will help decipher regulation of global gene expression. Here, we demonstrate that the cell-signaling inositol pyrophosphate 5-InsP 7 stabilizes mRNAs that are normally committed to decay pathways by NUDT3-mediated removal of the protective 5′ cap. We demonstrated this effect of 5-InsP 7 in vitro using recombinant NUDT3. Then, we applied pharmacological, genetic, and chemical tools to manipulate cellular levels of 5-InsP 7 , thereby showing it to enhance mRNA stability in intact cells. We further demonstrate mRNA stabilization is paralleled by increased abundance of P bodies, which are membraneless condensates that sequester mRNAs from the translating pool. Our demonstration that 5-InsP 7 regulates mRNA structure and stability, as well as P-body dynamics, illuminates cell-signaling oversight of cellular homeostasis.