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InsP 7 is a small-molecule regulator of NUDT3-mediated mRNA decapping and processing-body dynamics

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Sahu Soumyadip, Wang Zhenzhen, Jiao Xinfu, Gu Chunfang, Jork Nikolaus, Wittwer Christopher, Li Xingyao, Hostachy Sarah, Fiedler Dorothea, Wang Huanchen, Jessen Henning J., Kiledjian Megerditch, Shears Stephen B.,
Project Discovery and mechanistic dissection of novel signaling pathways controlling phosphate homeostasis in eukaryotes
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Original article (peer-reviewed)

Journal Proceedings of the National Academy of Sciences
Volume (Issue) 117(32)
Page(s) 19245 - 19253
Title of proceedings Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1922284117

Open Access

URL https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431097/
Type of Open Access Repository (Green Open Access)

Abstract

Regulation of enzymatic 5′ decapping of messenger RNA (mRNA), which normally commits transcripts to their destruction, has the capacity to dynamically reshape the transcriptome. For example, protection from 5′ decapping promotes accumulation of mRNAs into processing (P) bodies—membraneless, biomolecular condensates. Such compartmentalization of mRNAs temporarily removes them from the translatable pool; these repressed transcripts are stabilized and stored until P-body dissolution permits transcript reentry into the cytosol. Here, we describe regulation of mRNA stability and P-body dynamics by the inositol pyrophosphate signaling molecule 5-InsP 7 (5-diphosphoinositol pentakisphosphate). First, we demonstrate 5-InsP 7 inhibits decapping by recombinant NUDT3 (Nudix [nucleoside diphosphate linked moiety X]-type hydrolase 3) in vitro. Next, in intact HEK293 and HCT116 cells, we monitored the stability of a cadre of NUDT3 mRNA substrates following CRISPR-Cas9 knockout of PPIP5Ks (diphosphoinositol pentakisphosphate 5-kinases type 1 and 2, i.e., PPIP5K KO), which elevates cellular 5-InsP 7 levels by two- to threefold (i.e., within the physiological rheostatic range). The PPIP5K KO cells exhibited elevated levels of NUDT3 mRNA substrates and increased P-body abundance. Pharmacological and genetic attenuation of 5-InsP 7 synthesis in the KO background reverted both NUDT3 mRNA substrate levels and P-body counts to those of wild-type cells. Furthermore, liposomal delivery of a metabolically resistant 5-InsP 7 analog into wild-type cells elevated levels of NUDT3 mRNA substrates and raised P-body abundance. In the context that cellular 5-InsP 7 levels normally fluctuate in response to changes in the bioenergetic environment, regulation of mRNA structure by this inositol pyrophosphate represents an epitranscriptomic control process. The associated impact on P-body dynamics has relevance to regulation of stem cell differentiation, stress responses, and, potentially, amelioration of neurodegenerative diseases and aging.
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