Abstract:Inositol pyrophosphates, such as diphosphoinositol pentakisphosphate (IP7), are conserved eukaryotic signaling molecules that possess pyrophosphate and monophosphate moieties. Generated predominantly by inositol hexakisphosphate kinases (IP6Ks), inositol pyrophosphates can modulate protein function by posttranslational serine pyrophosphorylation. Here, we report inositol pyrophosphates as novel regulators of cytoplasmic dynein-driven vesicle transport. Mammalian cells lacking IP6K1 display defects in dynein-de… Show more
“…Further studies will be required to measure the reversibility of protein pyrophosphorylation and isolate any relevant bona fide phosphatases. Remarkably, protein pyrophosphorylation has already been linked to the regulation of diverse biological phenomena ranging from glycolysis , rRNA synthesis (Thota et al 2015), viral particle release (Azevedo et al 2009), and dynein-driven trafficking (Chanduri et al 2016). Although 5-IP 7 , 1-IP 7 , and even IP 8 show similar capacities for effecting protein pyrophosphorylation in vitro, the fact that 1-IP 7 , but not 5-IP 7 pyrophosphorylates and activates interferon regulatory factor 3 (IRF3) suggests some degree of stereo-selectivity between the various PP-IPs (Pulloor et al 2014).…”
Section: The Modes Of Action Of the Inositol Pyrophosphatesmentioning
Inositol pyrophosphates (PP-IPs) such as 5-diphosphoinositol pentakisphosphate (5-IP 7 ) are inositol metabolites with high-energy phosphoanhydride bonds. The formation of PP-IPs is catalyzed by two groups of enzymes, the IP6 kinases and the PPIP5 kinases, which both phosphorylate inositol hexakisphosphate (IP 6 ). In mammals, PP-IPs are implicated in diverse biological phenomena including cellular growth, vesicular trafficking, apoptosis, and metabolic homeostasis. Mechanistically, all the diverse actions of PP-IPs proceed in one of two ways: the PP-IPs modulate the activity of their target proteins either through allosteric binding or protein pyrophosphorylation. In this review, we highlight recent advances in our understanding of the pleiotropic functions of the mammalian PP-IPs and the metabolic enzymes that produce them. We also discuss some future challenges in the exploration of areas where PP-IPs play important but unknown roles in physiology and disease.ARTICLE HISTORY
“…Further studies will be required to measure the reversibility of protein pyrophosphorylation and isolate any relevant bona fide phosphatases. Remarkably, protein pyrophosphorylation has already been linked to the regulation of diverse biological phenomena ranging from glycolysis , rRNA synthesis (Thota et al 2015), viral particle release (Azevedo et al 2009), and dynein-driven trafficking (Chanduri et al 2016). Although 5-IP 7 , 1-IP 7 , and even IP 8 show similar capacities for effecting protein pyrophosphorylation in vitro, the fact that 1-IP 7 , but not 5-IP 7 pyrophosphorylates and activates interferon regulatory factor 3 (IRF3) suggests some degree of stereo-selectivity between the various PP-IPs (Pulloor et al 2014).…”
Section: The Modes Of Action Of the Inositol Pyrophosphatesmentioning
Inositol pyrophosphates (PP-IPs) such as 5-diphosphoinositol pentakisphosphate (5-IP 7 ) are inositol metabolites with high-energy phosphoanhydride bonds. The formation of PP-IPs is catalyzed by two groups of enzymes, the IP6 kinases and the PPIP5 kinases, which both phosphorylate inositol hexakisphosphate (IP 6 ). In mammals, PP-IPs are implicated in diverse biological phenomena including cellular growth, vesicular trafficking, apoptosis, and metabolic homeostasis. Mechanistically, all the diverse actions of PP-IPs proceed in one of two ways: the PP-IPs modulate the activity of their target proteins either through allosteric binding or protein pyrophosphorylation. In this review, we highlight recent advances in our understanding of the pleiotropic functions of the mammalian PP-IPs and the metabolic enzymes that produce them. We also discuss some future challenges in the exploration of areas where PP-IPs play important but unknown roles in physiology and disease.ARTICLE HISTORY
“…First and foremost, it requires the synthesis of 32 P-radiolabelled inositol pyrophosphates such as radiolabelled 5-diphosphoinositol pentakisphosphate (5-[β- 32 P]IP 7 ); although straightforward, preparing one's own radiolabelled chemicals requires a commitment not commonly found in today's young researchers. Consequently, any effort aiming to study protein pyrophosphorylation is commendable, including the report by Chanduri et al [9] published in a recent issue of the Biochemical Journal . Figure 1.Protein pyrophosphorylation is generate by a two-step mechanism.The serine residue (S, bold) is initially phosphorylated by CK2 that generates a phosphoserine residue using ATP (P, blue).…”
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confidence: 99%
“…Chanduri et al [9] mainly, but not exclusively, used the genetic model of mouse embryonic fibroblasts (MEFs) derived from ip6k1 −/− mice in their study. The knockout of IP6K1 (inositol hexakisphosphate kinase 1) results in a decrease of inositol pyrophosphate levels in ip6k1 − / − MEFs [10].…”
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confidence: 99%
“…The expression of active, but not inactive, IP6K1 rescued these defects, demonstrating that inositol pyrophosphates are required for endosomal sorting of transferrin and its accumulation in the ERC. Furthermore, Chanduri et al [9] have tracked vesicular movement in vivo using a specific fluorescence sensor, demonstrating that the speed of fluorescent endosomes is significantly lower in ip6k1 − / − MEFs. Another assay used by the authors to demonstrate altered intracellular vesicular movement is phagosome distribution.…”
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confidence: 99%
“…Another assay used by the authors to demonstrate altered intracellular vesicular movement is phagosome distribution. After allowing latex beads to be phagocytized by primary macrophages isolated from ip6k1 − / − and WT mice, a greater number of phagosomes in nuclear proximity was observed in macrophages collected from WT mice [9]. …”
Genetic ablation of inositol pyrophosphate synthesis has established the fundamental importance of this class of molecules to the eukaryote cell. These studies, however, must be complemented by cell biology and biochemical approaches to appreciate the signalling involved in the processes regulated by inositol pyrophosphates. A recent study by Chanduri et al. published in the Biochemical Journal, by integrating multiple experimental approaches, demonstrated that inositol pyrophosphates regulate intracellular vesicular movement. In particular, the vesicular transport along the microtubule that is driven by the motor protein complex dynein. Importantly, one subunit of this cellular motor, dynein 1 intermediate chain 2, undergoes serine pyrophosphorylation, a post-translational modification driven by inositol pyrophosphates. The pyrophosphorylation status of this dynein intermediate chain regulates its interaction with dynactin, which recruits the motor to vesicles. This mechanistically might explain how inositol pyrophosphates control intracellular membrane trafficking. By dissecting the serine pyrophosphorylation process, this work increases our awareness of this modification, underappreciated by the scientific literature but probably not by the eukaryotic cell.
Inositol pyrophosphates are small, diffusible signaling molecules that possess the most concentrated three-dimensional array of phosphate groups in Nature; up to eight phosphates are crammed around a six-carbon inositol ring. This review discusses the physico-chemical properties of these unique molecules, and their mechanisms of action. Also provided is information on the enzymes that regulate the levels and hence the signaling properties of these molecules. This review pursues the idea that many of the biological effects of inositol pyrophosphates can be rationalized by their actions at the interface of cell signaling and metabolism that is essential to cellular and organismal homeostasis.
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