Phosphoinositide turnover in Toll-like receptor signaling and trafficking.

Abstract

Lipid components in biological membranes are essential for maintaining cellular

function. Phosphoinositides, the phosphorylated derivatives of

phosphatidylinositol (PI), regulate many critical cell processes involving

membrane signaling, trafficking, and reorganization. Multiple metabolic pathways

including phosphoinositide kinases and phosphatases and phospholipases tightly

control spatio-temporal concentration of membrane phosphoinositides. Metabolizing

enzymes responsible for PI 4,5-bisphosphate (PI(4,5)P2) production or degradation

play a regulatory role in Toll-like receptor (TLR) signaling and trafficking.

These enzymes include PI 4-phosphate 5-kinase, phosphatase and tensin homolog, PI

3-kinase, and phospholipase C. PI(4,5)P2 mediates the interaction with target

cytosolic proteins to induce their membrane translocation, regulate vesicular

trafficking, and serve as a precursor for other signaling lipids. TLR activation

is important for the innate immune response and is implicated in diverse

pathophysiological disorders. TLR signaling is controlled by specific

interactions with distinct signaling and sorting adaptors. Importantly, TLR

signaling machinery is differentially formed depending on a specific membrane

compartment during signaling cascades. Although detailed mechanisms remain to be

fully clarified, phosphoinositide metabolism is promising for a better

understanding of such spatio-temporal regulation of TLR signaling and

trafficking.