Phagocytosis Proteins

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 Phagocytosis Proteins Background


From eukaryotic single celled organisms to the cells of multicellular organisms, multiple mechanisms have been developed for the internalization of a large variety of particles. Particles <0.5 µm in size can be internalized via receptor mediated endocytosis or pinocytosis; phagocytosis is the process by which cells internalize particles larger than 0.5 µm. In lower unicellular organisms such as Entamoeba histolytica, Dictyostelium discoideum, and Paramecium species, phagocytosis is crucial for the internalization of food micro-organisms from their surrounding environment, which are then broken down to provide nutrients for cell survival. The phagocytosis process in mammals could have evolved from such an ancient mechanism. In Drosophila melanogaster and Caenorhabditis elegans, phagocytosis is mainly employed to remove dead cells from the organism.

In mammals, phagocytosis mainly occurs in the specialized cells called "professional phagocytes" (macrophages, dendritic cells and neutrophils) of the immune system. They act as the primary line of host defense against invading pathogens and exogenous materials. When a nonself material enters the body, professional phagocytes are chemotactically attracted to the site of invasion, engulf the particle, and kill it when appropriate. In macrophages and dendritic cells, nonself antigens are processed and presented on the cell surface to initiate the adaptive immune response. Professional phagocytes participate also in clearing the massive numbers of cells that die from apoptosis during development. In addition to professional phagocytes, some microorganisms such as Listeria monocytogenes and Yersinia species can induce phagocytosis by expressing ligands for endogenous receptors on nonprofessional phagocytes (in this case epithelial cells), allowing their recognition and ingestion by these cells. These pathogens use phagocytosis as a cellular entry pathway.

Phagosome formation

The process of phagocytosis can be dissected into several steps based on the morphological and biochemical changes that take place during the phagosome maturation process. In mammals, the process is initiated by binding of specific cellular receptors with ligands on the target particle. There are different types of cellular receptors expressed on macrophages for this purpose including the mannose 6-phosphate receptors (M6PR), Fc receptors (Fc), and complement receptors. Interaction between the target ligands and the cell surface receptors induces localized actin polymerization at the plasma membrane. Actin associated proteins and several signal transduction mechanisms participate in actin sheath formation. As a result, lamellipodial extensions of the plasma membrane start forming around the target particle. Finally, the nascent phagosome is formed when the plasma membrane extensions wrap completely around the target particle, and there is membrane fusion at the tip of the internalized particle-containing membrane vesicle. The process of ingestion is thought to occur by a "zipper" model, in which the particle-ligand macrophage-receptor interaction all around the particle creates a very close apposition with the phagosome membrane. In general, most of the nascent phagosome membrane originates from the plasma membrane. Under certain circumstances, particularly when large particles are taken up, several other additional membrane sources such as recycling endosomes and VAMP7-containing late endosomes have been proposed to participate in phagosome formation. Endoplasmic reticulum (ER) membrane also has been proposed as a source of membrane for the nascent phagosome, but its involvement is still controversial.

Phagosome maturation

Once the nascent phagosome is formed, the actin sheath of the phagosome disappears, and the phagosome proceeds through a series of fusion and fission events with vesicles derived from the endocytic pathway, such as early sorting endosomes (SE), late endosomes (LE), and lysosomes in a sequential manner.

The endocytic pathway

The phagosome maturation process entirely depends on the interaction with the endocytic pathway. Sorting endosomes are the first in the endocytic pathway to interact with phagosomes. They are poor in proteases and are mildly acidic with a pH of 6.0. These organelles are tubulovesicular and carry RAB5 and the early endosome antigen 1 (EEA1) marker proteins. The nascent phagosome first interacts with sorting endosome and acquires sorting endosome specific marker proteins. In addition, plasma membrane receptors are recycled back to the plasma membrane via recycling endosomes (RE), which are characterized by the presence of the RAB11 protein. Other molecules that are destined for degradation are transported from sorting endosomes to late endosomes.

The late endosomes are more acidic with a pH of 5.5 and are comparatively rich in hydrolytic enzymes. Late endosomes can be identified by the presence of specific marker proteins such as Rab7, Rab9, M6PR, and lysosomal associated membrane proteins (LAMPs). The late endosomes also carry characteristic small intraluminal vesicles called multivesicular bodies (MVBs) which contain transmembrane proteins destined for degradation. It is not clear how the components are transported from sorting to late endosomes. It could be via vesicles or, alternatively, the sorting endosome might gradually mature into a late endosome through a series of fission and fusion events. In addition to sorting endosomes, the late endosome receives hydrolytic enzymes through the biosynthetic pathway from the trans-Golgi network (TGN), and these enzymes are then sorted and transported to the lysosomes or back to the TGN via retrograde transport. Phagosomes interact with late endosomes and receive hydrolytic enzymes as well as late endosomal marker proteins.

Lysosomes are the next and final organelle in the endocytic pathway with which phagosomes interact. They are extremely acidic (pH< 5.5) and loaded with hydrolytic enzymes. It was initially thought that LAMPs and the hydrolytic enzyme cathepsin D are unique to lysosomes, but it is now apparent that they are also present in the late endosomes. Lysosomes degrade components received via endocytosis and also fuse with phagosomes and autophagosomes for the same purpose.

As a result of the sequential fusion events, phagosomes gradually gain membrane and luminal components of the endosomes and lysosomes, and are turned into a hybrid organelle called the phagolysosome. During this process, they acquire microbicidal properties such as a very low pH, hydrolytic enzymes, and the ability to generate toxic oxidative compounds, which eventually kill and digest the ingested cargo.