FIGURE 1.

Regulation of phagosomal pH in phagocytes. V-ATPases hydrolyze ATP to pump 3H⁺ into the phagosome. As the V-ATPase is electrogenic, its continued operation is dependent on parallel counter-ion influxes. These can be provided by rheogenic anion antiporters like ClC-7 and ClC-3 and/or through cation efflux via channels such as TPC2 and TRPML1. Conversion of PI(3)P into PI(3,5)P₂ by PIKfyve regulates TRPML1, TCP-2 and possibly also the V-ATPase itself. A number of pathways promote the “leakage” of H⁺ out of phagosomes. These include monovalent and divalent cation/H⁺ antiporters (NHE and CHE) or symporters (NRAMP1), Hv1 H⁺-selective channels and amino acid-H⁺ cotransporters of the SLC family. In addition, H⁺ is consumed during antimicrobial activities by products of the NADPH oxidase to produce hydroxyl radicals, HOCl, and H₂O₂. Low luminal pH is required for the autoactivation of various phagosomal proteases and for protonation of microbicidal effectors.