ER-Mediated Phagocytosis
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ER-Mediated Phagocytosis

Phagocytosis, the process by which cells engulf foreign particles, occurs in eukaryotes ranging from unicellular organisms, which use it for nutrition, to mammals, where it plays a key role in innate immunity. The remarkable phagocytic capacity of Macrophages is illustrated by their ability to internalize particles that can be as large as themselves without impairing their function and viability. Although most of the models of Phagocytosis present the plasma membrane as the main source of membrane for phagosome formation, the observation that Macrophages can internalize particles as large as themselves raise questions about the source of membrane to carry out this process. Indeed, in these cases, the plasma membrane is not sufficient and other sources of membranes have to be recruited to the cell surface to contribute to phagosome formation. Focal exocytosis of membrane at the site of phagosome formation offers a partial solution to the ‘membrane economy’ problem associated with Phagocytosis. Although lysosomes and recycling endosomes are able to supply membrane during Phagocytosis, the ER (Endoplasmic Reticulum) serves as the main source of intracellular membrane contributing to phagosome formation in Macrophages, in a process known as ER-mediated Phagocytosis and this has significant biological consequences. Neutrophils, however, apparently use a more conventional plasmamembrane-mediated type of Phagocytosis (Ref.1, 2, 3 & 4).

When Macrophages encounter pathogens, they bind and internalize them via Phagocytic Receptors. This triggers a diversity of signals that lead to rearrangement of the Actin cytoskeleton, a step controlled by various small GTPases of the Rho/Rac family. Signalling events rapidly lead to cytoskeletal reorganization and concomitant pseudopodia extension. During this process, the ER is recruited close to the surface where it fuses with the plasma membrane and opens at the site of particle contact. The particle then slides into the opened ER and the plasma membrane is resealed at the end of the entry process. This leads to the formation of phagosomes made largely of ER, a process that minimizes the use of the highly specialized plasma membrane, providing another mechanism for the cell to control its membrane economy. ER-mediated Phagocytosis is regulated in part by PI3K (Phosphatidylinositde-3 Kinase) and used for the internalization of intracellular pathogens, regardless of their final trafficking in the host. PI3K is required for the recruitment and fusion of recycling endosomes with the nascent phagocytic cup. The cascade of inositol lipid turnover stimulated during Phagocytosis occurs at the plasma membrane, and the resulting DAG (Diacylglycerol) is converted into phosphatidic acid on the phagosomal membrane. PI3K is required for coordinating exocytic membrane insertion and pseudopodia extension.  It also participates in the deactivation of PAK1, a step needed for phagosome closure (Ref.1, 4 & 5).

Newly formed phagosomes then rapidly interact with endocytic organelles in a highly regulated process allowing phagolysosome biogenesis. During the process, successive waves of ER become associated with maturing phagosomes. Rapidly after their formation at the cell surface, phagosomes mature into phagolysosomes through a series of transient fusion events with EE (Early Endosomes), LE (Late Endosomes) and Lysosomes. This maturation process allows phagosomes to acquire some of their microbicidal properties and the ability to process antigens. In the phagolysosome, the hydrolytic enzymes generate pathogen-derived peptides that are presented to T-Cells via MHC (Major Histocompatibility Complex) Class-I and Class-II molecules. Antigen presentation represents the intersection of the innate and adaptive immune systems. Phagocytosis also triggers the release of inflammatory mediators, some of which further instruct the adaptive immune response (Ref.6).

Antigen, taken up via ER-mediated Phagocytosis by Macrophages, can enter the conventional pathway for presentation by MHC-I, either by rupture of the phagosomal membrane or by a selective transport mechanism, that requires the Proteasome machinery, TAP (Transporter Associated with Antigen Processing), and the newly synthesized MHC-I molecules. Newly synthesized MHC-I heavy chains assemble in the ER with the membrane-bound protein Calnexin. When this complex binds Beta2-Microglobulin, the partly folded MHC-I molecule is released from Calnexin and then associates with the TAP-associated protein Tapasin and the chaperone protein Calreticulin. Antigens from pathogens, generated through the action of hydrolases (H) in the phagosome lumen, are translocated to the cytoplasm by the transporter protein, SEC61. There, the antigens are processed by the Proteasome to generate the appropriate peptides. These peptides are then translocated to the ER lumen, through the TAP complex. The MHC-I molecule is retained in the ER until it binds a pathogen-derived peptide, which completes the folding of the molecule. The peptide-MHC-I molecule complex is then released from Tapasin and Calreticulin, leaves the ER, and is transported to the cell surface for presentation to CD8+ T-Cells. Transport of the peptide-MHC complex to the cell surface alerts the immune system to the presence of pathogens. Peptides generated from bacteria in the phagolysosomes are presented by MHC-II to CD4+ T-Cells. The pathogen-derived peptides are bound to MHC-II molecules, which have been transported to the vesicles via the ER and the Golgi apparatus. The peptide-MHC-II complex is transported to the cell surface in outgoing vesicles and is presented to CD4+ T-Cells (Ref.3 & 6).

ER-mediated Phagocytosis is a widely used process in Macrophages for the internalization of both inert particles and intracellular pathogens, including Salmonella typhimurium and Leishmania donovani, which are all found within phagosomes displaying ER characteristics. Several pathogenic microorganisms find a safe niche within phagocytic vacuoles and are able to control phagosome maturation to their advantage (Ref.6). To ensure their survival within host cells, pathogens have evolved ways to inhibit the maturation of ER-derived Phagosomes at different stages during phagolysosome biogenesis and thus avoid the lytic environment of phagolysosomes. Pathogens, such as Legionella and Brucella, would exert their effect on Phagolysosome biogenesis very early in the process, when they are still in ER-derived compartments, while others like Salmonella, Mycobacteria, and Leishmania would allow the initiation of phagosome maturation and block the completion of this process later on. In neutrophils, where pathogens are rapidly killed, the ER is not used as a major source of membrane for Phagocytosis (Ref.1, 5 & 7).