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Post-translational modifications of proteins (PTMs) introduce an extra layer of complexity to cellular regulation. Although phosphorylation of serine, threonine, and tyrosine residues is well-known as PTMs, lysine is, in fact, the most heavily modified amino acid, with over 30 types of PTMs on lysine having been characterized. One of the most recently discovered PTMs on lysine residues is polyphosphorylation, which sees linear chains of inorganic polyphosphates (polyP) attached to lysine residues. The labile nature of phosphoramidate bonds raises the question of whether this modification is covalent in nature. Here, we used buffers with very high ionic strength, which would disrupt any non-covalent interactions, and confirmed that lysine polyphosphorylation occurs covalently on proteins containing PASK domains (polyacidic, serine-, and lysine-rich), such as the budding yeast protein nuclear signal recognition 1 (Nsr1) and the mammalian protein nucleolin. This Matters Arising Response paper addresses the Neville et al. (2024) Matters Arising paper, published concurrently in Molecular Cell. [Display omitted] [ABSTRACT FROM AUTHOR]

Cellular synthesis of phytic acid sequesters phosphates in the sugar inositol. Phytic acid in soil represents the most abundant form of organic phosphates. The supplementation of phytase or phytase-producing organisms has been considered as a strategy to improve usable soil phosphates. However, the impacts on the environmental flow of inositol, which is generated along with phosphate by phytase, have not been examined. In this review, we discuss the origin and nature of inositol produced in soil and the several possible destinations of inositol released by phytase activities. We emphasise how an improved understanding of soil inositol flow could help to provide new solutions to the phosphate shortage problem in agriculture., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Inositol hexakisphosphate (InsP 6 ), also known as phytic acid, is a potent chelator of bivalent cations. Intracellular InsP 6 molecules are associated with magnesium. Calcium is the prevalent bivalent cation outside the cell and its association with InsP 6 could lead to the formation of insoluble complexes. To avoid the formation of dangerous InsP 6 /Calcium precipitates in the bloodstream, mammals must possess a robust InsP 6 phosphatase in their plasma. Here we identify the Multiple Inositol Polyphosphate Phosphatase 1 ( MINPP1 ) as the InsP 6 phosphatase present in human plasma., Competing Interests: The authors declare that there are no conflicts of interest present., (Copyright: © 2024 by the authors.)

HDACs (histone deacetylase) play a crucial role in regulating gene expression, and the inhibition of these enzymes is gaining attention as a promising therapeutic approach for cancer treatment. Despite their significant physiological and clinical importance, the mechanisms of HDAC activation remain poorly understood. This study reveals that inositol polyphosphate multikinase (IPMK) is essential for activating HDAC1 and HDAC3 in cell lines and mice. IPMK deletion or inactivation of its kinase activity selectively impairs HDAC1/3's deacetylase activity, significantly influencing gene expression. Disruption of the IPMK-HDAC1/3 epigenetic axis results in transcriptional upregulation of matrix metalloproteinase (MMP) genes, exacerbating cell and intestinal permeability. Remarkably, treatment of IPMK KO cells with cell-permeable inositol hexaphosphate (InsP6) rescues these defects. This study elucidates the role of IPMK's kinase activity in HDAC1/3 activation and its implications for intestinal barrier function.