Type III phosphatidylinositol 4 kinases: structure, function, regulation, signalling and involvement in disease

Abstract

Many important cellular functions are regulated by the selective recruitment of proteins to intracellular membranes mediated by specific interactions with lipid phosphoinositides. The enzymes that generate lipid phosphoinositides therefore must be properly positioned and regulated at their correct cellular locations. Phosphatidylinositol 4 kinases (PI4Ks) are key lipid signalling enzymes, and they generate the lipid species phosphatidylinositol 4-phosphate (PI4P), which plays important roles in regulating physiological processes including membrane trafficking, cytokinesis and organelle identity. PI4P also acts as the substrate for the generation of the signalling phosphoinositides phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3). PI4Ks also play critical roles in a number of pathological processes including mediating replication of a number of pathogenic RNA viruses, and in the development of the parasite responsible for malaria. Key to the regulation of PI4Ks is their regulation by a variety of both host and viral protein-binding partners. We review herein our current understanding of the structure, regulatory interactions and role in disease of the type III PI4Ks.

Sac1, a lipid phosphatase at the interface of vesicular and nonvesicular transport

“…Although normally enriched at the Golgi and PM, PI4P is detected to some degree on most intracellular membranes . The presence of multiple, distinct PI4P pools is dictated by PI4Ks . Yeast and fruit flies encode 3 different PI4Ks, whereas mammals have 4.…”

“…6,9,[45][46][47][48] The presence of multiple, distinct PI4P pools is dictated by PI4Ks. 5,8,[49][50][51][52][53] [67][68][69][70][71][72] PI4KIIα and PI4KII also localize to the TGN, where they participate in post-Golgi trafficking, 5,6,70 whereas PI4KIIβ and Lsb6 are also found at the PM. [73][74][75][76] The genetics of PI4Ks differs in different organisms.…”

Phosphatidylinositol 4-Kinase Enzymes: Functional Roles and Potential for Drug Target

“…In contrast, several studies have described PI-4KII functions in post-TGN traffic through PI(4)P biosynthesis and direct binding to clathrin adaptors AP-1 and AP-3 [19], both pathways that contribute to endo-lysosomal traffic (Refer Fig.1). PI-4KIIα controls LE traffic of the EGFR [20], endolysosomal traffic mediated by AP-3 and of lysosomal membrane proteins and hydrolases such as the enzyme -glucocerebosidase [21].This explains the similar effects of PI-4KII and PI-4KII depletion on EGFR degradation and LE traffic. Keeping in mind that most PI4KIIα and a substantial portion of PI-4KIIβ exist as membrane proteins in the cytoplasm owing to the palmitoylated cysteine residues, it appears inevitable that the nuclear PI4KIIα and IIβ also exist as membrane proteins in the nucleus.…”

Characterization of the c10orf76‐PI4KB complex and its necessity for Golgi PI4P levels and enterovirus replication

“…The phosphoinositide species phosphatidylinositol 4-phosphate (PI4P) is widely distributed and involved in the coordinated regulation of membrane trafficking, cell division, and lipid transport [1,2]. PI4P in humans is generated through the action of four phosphatidylinositol 4-kinases: PI4KIIa (PI4K2A), PI4KIIb (PI4K2B), PI4KIIIa (PI4KA), and PI4KIIIb (PI4KB) [6][7][8]. PI4P in humans is generated through the action of four phosphatidylinositol 4-kinases: PI4KIIa (PI4K2A), PI4KIIb (PI4K2B), PI4KIIIa (PI4KA), and PI4KIIIb (PI4KB) [6][7][8].…”