Insights into the roles of inositol hexakisphosphate kinase 1 (IP6K1) in mammalian cellular processes

Abstract

Inositol phosphates and their metabolites play a significant role in several biochemical pathways, gene expression regulation, and phosphate homeostasis. Among the different inositol phosphates, inositol hexakisphosphate (IP6) is a substrate of inositol hexakisphosphate kinases (IP6Ks), which phosphorylate one or more of the IP6 phosphate groups. Pyrophosphorylation of IP6 leads to the formation of inositol pyrophosphates, high-energy signaling molecules that mediate physiological processes through their ability to modify target protein activities, either by directly binding to their target protein or by pyrophosphorylating protein serine residues. 5-diphosphoinositol pentakisphosphate, the most abundant inositol pyrophosphate in mammals, has been extensively studied and found to be significantly involved in a wide range of physiological processes. Three IP6K (IP6K1, IP6K2, and IP6K3) isoforms regulate IP7 synthesis in mammals. Here, we summarize our current understanding of IP6K1's roles in cytoskeletal remodeling, trafficking, cellular migration, metabolism, gene expression, DNA repair, and immunity. We also briefly discuss current gaps in knowledge, highlighting the need for further investigation.

Keywords: 5-IP7; cell migration; gene expression; inositol phosphate; inositol pyrophosphates; metabolism; phosphorylation.

Figure 1

The pyrophosphorylation role of IP6K1 and 5-IP7.A, inositol hexakisphosphate kinase 1 (IP6K1) phosphorylates inositol hexakisphosphate (IP6) on phosphorylated carbon number 5. This ATP-dependent reaction, termed pyrophosphorylation, is characterized by the addition of a phosphate group to a pre-existing phosphorylation mark (P). The product of this reaction is the inositol pyrophosphate 5-diphosphoinositol pentakisphosphate (5-IP7). B, 5-IP7 pyrophosphorylates its target proteins independently, without the need for ATP or protein kinases. Target proteins must first be primed by the action of a protein kinase, which phosphorylates a serine residue (Ser) within the target protein. This ATP-dependent phosphorylation tags the target protein for further pyrophosphorylation by 5-IP7 in the presence of Mg²⁺.

Figure 2

Roles of IP6K1 in trafficking, migration, and cytoskeleton remodeling. (1) Migration. IP6K1 binds α-actinin localized at focal adhesions, promoting its phosphorylation by focal adhesion kinase (FAK). 5-IP7 produced by IP6K1 binds to FAK and triggers its pyrophosphorylation and dimerization, thereby regulating interactions with the extracellular matrix, cell migration, and angiogenesis. In the nucleus, 5-IP7 enhances the expression of genes involved in cell-matrix interaction. (2) Cytoskeleton. 5-IP7, produced by the interaction of IP6K1 with actin-related protein 2 (Arp2), recruits the Arp2/3 inhibitor coronin and thereby disrupts actin filament production. (3) Trafficking. 5-IP7 triggers the pyrophosphorylation of dynein intermediate chain (IC), promoting dynein-dependent transport. 5-IP7 also triggers the pyrophosphorylation of adaptor protein 3 (AP3), blocking its interaction with the kinesin motor protein Kif3A and thus attenuating kinesin-dependent transport. Binding of 5-IP7 to the calcium sensor synaptotagmin 1 (SYT1) inhibits neurotransmitter exocytosis from neurons. Binding of IP6K1 to the guanine exchange factor GRAB prevents formation of the GRAB/Rab3A complex, thus inhibiting calcium-dependent neuroexocytosis. Binding of 5-IP7 to the phosphoinositide 3-kinase (PI3K) p85α subunit recruits adaptor protein 2 (AP2), triggering clathrin-mediated endocytosis and degradation of the sodium-potassium ATPase. 5-IP7, 5-diphosphoinositol pentakisphosphate; IP6K1, inositol hexakisphosphate kinase 1.

Figure 3

Roles of IP6K1 in gene expression and DNA repair. (1) DNA methylation. An IP6K1-mediated increase in 5-IP7 inhibits the histone lysine demethylase Jumonji domain containing 2C (JMJD2C). Inhibition of JMJD2C triggers the dissociation of JMJD2C from chromatin, thereby increasing trimethyl-histone H3 lysine 9 (H3K9me3) levels and inhibiting the transcription of target genes. 5-IP7 also inhibits protein kinase B (AKT), resulting in increased methylation of imprinted genes. (2) Recombination. 5-IP7 plays a crucial role in the progression and completion of homologous recombination (HR) DNA repair following DNA damage. (3) Gene expression. High levels of cell-membrane PA trigger the translocation of IP6K1 into the nucleus where it increases H3K9me3 levels in the ISYNA1 promoter region. This results in inhibition of ISYNA1 expression and decreased de novo synthesis of myo-inositol. (4) Translation. IP6K1 localized to the ribosome near the translation initiation complex can interact with the mRNA de-capping complex. This interaction decreases the number of mRNA de-capping proteins, consequently blocking mRNA translation and increasing the formation of P-bodies. (5) Protein degradation. Under stress conditions, the production of 5-IP7 by IP6K1 causes the dissociation and activation of CRL4 from the signalosome. Activated CRL4 ubiquitylates and degrades target proteins involved in nucleotide excision repair. 5-IP7, 5-diphosphoinositol pentakisphosphate; IP6K1, inositol hexakisphosphate kinase 1.

Figure 4

Roles of IP6K1 in metabolism and immunity. (1) Insulin secretion: High levels of glucose increase the ATP/ADP ratio in pancreatic β-cells; this change is sensed by IP6K1, which triggers the production of 5-IP7. Following neuronal stimulation, acetylcholine stimulates muscarinic M3 receptors (M3R) on β-cells triggering the sequential activation of the G-protein αq-subunit (G αq), PLC, PKC, and PKD to phosphorylate IP6K1. Phosphorylated IP6K1 is activated to produce high levels of 5-IP7. 5-IP7 binds Ca²⁺ ions and thereby frees synaptotagmin 7 (SYT7) to interact with PIP2, inducing insulin exocytosis. Note: under basal conditions, 5-IP7 binds SYT7 and prevents its interaction with PIP2. Secreted insulin binds to insulin receptors on β-cells, triggering the activation of AKT. (2) Obesity: 5-IP7 inhibits AKT and AMP-activated protein kinase (AMPK), causing an increase in body weight and insulin resistance in diet-induced obese mice. (3) Mitochondrial dysfunction: Inhibition of AKT by 5-IP7 in cardiomyocytes is linked to attenuation of mitochondrial function and biogenesis. (4) Lipolysis: In adipose tissue, the phosphorylation of IP6K1 on a PKA/PKC motif triggers its binding to the lipolytic regulator protein perilipin1 (PLIN1), thereby regulating lipolysis. 5-IP7 also binds to the adiponectin-DsbA-L complex and enhances its interaction with the Erp44/Ero1-Lα complex to trigger cellular retention and degradation of adiponectin. (5) Neutrophil defenses: In neutrophils, IP6K1 was shown to inhibit the PIP3-mediated membrane translocation of AKT, decreasing phagocytic and bactericidal capabilities. (6) Lung damage: During pneumonia infection, IP6K1 mediates the production of inorganic polyphosphates (polyP) in platelets. PolyP production leads to the formation of infection-induced neutrophil-platelet aggregates in the alveolar spaces, consequently contributing to lung damage. PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-triphosphate; PKC, protein kinase C; PKD, protein kinase D; PLC, phospholipase C.