Phagosome Maturation


Pathway Description

Phagosome maturation is the process by which internalized particles (such as bacteria and apoptotic cells) are trafficked into a series of increasingly acidified membrane-bound structures, leading to particle degradation. Phagosome maturation starts immediately after, and possibly even before, phagosome sealing. After scission from the surface membrane, the phagosome undergoes sequential fusion with early endosomes, late endosomes and lysosomes. Remodeling of the membrane of the phagosome is accompanied by acute changes in the composition of its lumen, which becomes a highly acidic, oxidative and degradative milieu.

The GTPase Rab5 integrates the targeting, tethering and fusion of early endosomes and interacts using multiple effectors, including the VPSS34 complex, early endosome antigen 1 (EEA1) and SNARE proteins. Acidification of the phagosome occurs via a vATPase that translocates H+ across the membrane bilayer. Phagosomal acidification creates a hostile environment that impedes microbial growth. The ESCRT complexes function to sort endosomal proteins into the luminal vesicles of multivesicular bodies. The multivesicular bodies (MVB) generated by the combined action of the ESCRT complexes are a subset of endosomes that have intraluminal vesicles and are thought to be important in receptor down-regulation and in antigen presentation as well as formation of the intermediate phagosome.

Once recycling proteins are removed, the phagosome proceeds to the late stage, which is characterized by a more acidic lumen brought about by the insertion of additional proton-pumping v-ATPases. Recruitment of Rab7 by phagosomes is found to precede and to be essential for optimal fusion with lysosomes and other late-endocytic organelles. In addition, phagosomal association of RILP, which follows shortly after Rab7 recruitment, is also essential for fusion with late-endocytic compartments. The late phagosome is also enriched in proteases and lysosomal-associated membrane proteins (LAMPs), which are either imported from the Golgi complex or acquired by fusion with late endosomes.The maturation process culminates with the formation of the phagolysosome. The phagolysosome is formed by the fusion of the mature phagosome with a series of lysosomes through a Rab7 dependent process and are highly acidic (luminal pH values as low as 4.5 have been reported). Insertion of additional v-ATPases and tightening of the H+ leak account for the accentuated acidification. Phagolysosomes can be differentiated from late phagosomes by their paucity of LBPA or PI(3)P-enriched internal membranes, by their elevated mature cathepsin content and by their lack of mannose-6-phosphate receptors. When the membranes of the phagosome and lysosome meet, the contents of the lysosome explosively discharge, releasing a variety of macromolecules that degrade the contents. An additional model in phagosome formation/maturation involves the fusion of the endoplasmic reticulum (ER) with the membrane underneath phagocytic cups. Successive waves of ER become associated with maturing phagosomes during phagolysosome biogenesis. After phagocytosis, antigens are exported into the cytosol and degraded by the proteasome.