Phosphoinositides and phagocytosis

Abstract

Phosphoinositide 3 kinases (PI3Ks)*Abbreviation used in this paper: PI3K, phosphoinositide 3 kinase. are known as regulators of phagocytosis. Recent results demonstrate that class I and III PI3Ks act consecutively in phagosome formation and maturation, and that their respective products, phosphatidylinositol 3,4,5-trisphosphate (PI[3,4,5]P(3)) and phosphatidylinositol 3-phosphate (PI[3]P), accumulate transiently at different stages. Phagosomes containing Mycobacterium tuberculosis do not acquire the PI(3)P-binding protein EEA1, which is required for phagosome maturation. This suggests a possible mechanism of how this microorganism evades degradation in phagolysosomes.

Figure 1.

Phagocytosis of M. tuberculosis and an IgG-opsonized microorganism. The IgG-opsonized microorganism binds to Fcγ-receptors in the membrane of the phagocyte. This causes phosphorylation of the cytoplasmic part of the receptor and subsequent recruitment of a class I PI3K. The PI3K produces PI(3,4,5)P₃, which recruits proteins involved in the rearrangements of cortical actin that are necessary for membrane remodelling and phagosome formation. When the phagosome is sealed, PI(3,4,5)P₃ is rapidly dephosphorylated, and PI(3)P is formed by a class III PI3K, which is recruited to the early phagosome by the small GTPase Rab5 (Christoforidis et al., 1999). EEA1, a protein that promotes the tethering and fusion of early endocytic organelles, is also recruited by the interaction with PI(3)P and Rab5. Through exchange of molecules with cytosol, acquisition of cargo from the biosynthtic pathway and transient (“kiss-and-run”) fusion (red double arrows) with early endosomes (EE) and late endosomes (LE), the phagosome gradually matures (Desjardins et al., 1994). Eventually it fuses (blue double arrow) with a lysosome, thus forming a phagolysosome in which degradation of the microorganism ensues. Note that early phagosomes and EEs contain Rab5, whereas more mature phagosomes and LEs contain Rab7. M. tubercolusis also enters the phagocyte by phagocytosis, but the phagosome does not mature, and it does not acquire EEA1. The shedding of ManLAM, which intercalates into phagosomal and other membranes, contributes to the maturation arrest, possibly by preventing EEA1 recruitment.

Figure 2.

The structures of phosphatidylinositol (A) and ManLAM (B), a glycophosphatidylinositol from M. tuberculosis. Phosphatidylinositol can be phosphorylated in the 3, 4, or 5 positions of the inositol headgroup, as indicated with blue arrows. PI(3)P is phosphorylated at the 3 position, and PI(3,4,5)P₃ at the 3, 4, and 5 positions. Adapted from Vanhaesebroeck et al. (2001) and Gilleron et al. (2000).