Phagosome
In
A phagosome is formed by the fusion of the
However, some
Formation
Phagosomes are large enough to degrade whole bacteria, or
Phagosomes are formed when pathogens or
Opsonisation
Opsonins are molecular tags such as
Complement-mediated internalisation has much less significant membrane protrusions, but the downstream signalling of both pathways converge to activate Rho GTPases.[12] They control actin polymerisation which is required for the phagosome to fuse with endosomes and lysosomes.
Non-phagocytic cells
Other non-professional phagocytes have some degree of phagocytic activity, such as thyroid and bladder epithelial cells that can engulf erythrocytes and retinal epithelial cells that internalise retinal rods.[8] However non-professional phagocytes do not express specific phagocytic receptors such as FcR and have a much lower rate of internalisation.
Some invasive bacteria can also induce phagocytosis in non-phagocytic cells to mediate host uptake. For example,
Structure
As the membrane of the phagosome is formed by the fusion of the plasma membrane, the basic composition of the
Phagosomes can engulf artificial low-density latex beads and then purified along a sucrose concentration gradient, allowing the structure and composition to be studied.[15] By purifying phagosomes at different time points, the maturation process can also be characterised. Early phagosomes are characterised by Rab5, which transition into Rab7 as the vesicle matures into late phagosomes.
Maturation process
The nascent phagosome is not inherently bactericidal. As it matures, it becomes more acidic from pH 6.5 to pH 4, and gains characteristic protein markers and hydrolytic enzymes. The different enzymes function at various optimal pH, forming a range so they each work in narrow stages of the maturation process. Enzyme activity can be fine-tuned by modifying the pH level, allowing for greater flexibility. The phagosome moves along
Fusion may take minutes to hours depending on the contents of the phagosome; FcR or mannose receptor-mediated fusion last less than 30 minutes, but phagosomes containing latex beads may take several hours to fuse with lysosomes.[8] It is suggested that the composition of the phagosome membrane affects the rate of maturation. Mycobacterium tuberculosis has a very hydrophobic cell wall, which is hypothesised to prevent membrane recycling and recruitment of fusion factors, so the phagosome does not fuse with lysosomes and the bacterium avoids degradation.[18]
Smaller lumenal molecules are transferred by fusion faster than larger molecules, which suggests that a small aqueous channel forms between the phagosome and other vesicles during "kiss-and-run", through which only limited exchange is allowed.[8]
Fusion regulation
Shortly after internalisation, F-actin depolymerises from the newly formed phagosome so it becomes accessible to endosomes for fusion and delivery of proteins.[8] The maturation process is divided into early and late stages depending on characteristic protein markers, regulated by small Rab GTPases. Rab5 is present on early phagosomes, and controls the transition to late phagosomes marked by Rab7.[19]
Rab5 recruits PI-3 kinase and other tethering proteins such as Vps34 to the phagosome membrane, so endosomes can deliver proteins to the phagosome. Rab5 is partially involved in the transition to Rab7, via the CORVET complex and the HOPS complex in yeast.[19] The exact maturation pathway in mammals is not well understood, but it is suggested that HOPS can bind Rab7 and displace the guanosine nucleotide dissociation inhibitor (GDI).[20] Rab11 is involved in membrane recycling.[21]
Phagolysosome
The phagosome fuses with lysosomes to form a phagolysosome, which has various bactericidal properties. The phagolysosome contains reactive oxygen and nitrogen species (ROS and RNS) and hydrolytic enzymes. The compartment is also acidic due to proton pumps (v-ATPases) that transport H+ across the membrane, used to denature the bacterial proteins.
The exact properties of phagolysosomes vary depending on the type of phagocyte. Those in dendritic cells have weaker bactericidal properties than those in macrophages and neutrophils. Also, macrophages are divided into pro-inflammatory "killer" M1 and "repair" M2. The phagolysosomes of M1 can metabolise arginine into highly reactive nitric oxide, while M2 use arginine to produce ornithine to promote cell proliferation and tissue repair.[22]
Function
Pathogen degradation
Macrophages and neutrophils are professional phagocytes in charge of most of the pathogen degradation, but they have different bactericidal methods. Neutrophils have granules that fuse with the phagosome. The granules contain
Inflammation
Phagosome formation is tied to
The process is tightly regulated and the inflammatory response varies depending on the particle type within the phagosome. Pathogen-infected apoptotic cells will trigger inflammation, but damaged cells that are degraded as part of the normal tissue turnover do not. The response also differs according to the opsonin-mediated phagocytosis. FcR and mannose receptor-mediated reactions produce pro-inflammatory reactive oxygen species and arachidonic acid molecules, but CR-mediated reactions do not result in those products.[8]
Antigen presentation
Immature dendritic cells (DCs) can phagocytose, but mature DCs cannot due to changes in Rho GTPases involved in cytoskeleton remodelling.
Nutrient
Ancient single-celled organisms such as
Tissue clearance
Phagosomes degrade senescent cells and apoptotic cells to maintain tissue homeostasis.
Autophagosome
Bacterial evasion and manipulation
Many bacteria have evolved to evade the bactericidal properties of phagosomes or even exploit phagocytosis as an invasion strategy.
- Mycobacterium tuberculosis target M2 macrophages at the lower parts of the respiratory pathway, which do not produce ROS.[31] M. tuberculosis can also manipulate the signalling pathways by secreting phosphatases such as PtpA and SapM, which disrupt protein recruitment and block phagosome acidification.[8][32]
- Legionella pneumophila can re-model the phagosome membrane to imitate vesicles in other parts of the secretory pathway, so lysosomes do not recognise the phagosome and do not fuse with it. The bacterium secretes toxins that interfere with host trafficking, so the Legionella-containing vacuole recruits membrane proteins usually found on the endoplasmic reticulum or the ERGIC.[33] This re-directs secretory vesicles to the modified phagosome and deliver nutrients to the bacterium.
- Listeria monocytogenes secretes a pore-forming protein listeriolysin O so the bacterium can escape the phagosome into the cytosol. Listeriolysin is activated by the acidic environment of the phagosome.[34] In addition, Listeria secrete two phospholipase C enzymes that facilitate in phagosome escape.
See also
References
- ^ Robinson & Babcock 1998, p. 187 and Ernst & Stendahl 2006, pp. 7–10
- PMID 6942430.
- PMID 2252380.
- S2CID 83944695.
- PMID 18641659.
- S2CID 8962102.
- PMID 11765232.
- ^ PMID 10358769.
- ^ PMID 12792849.
- PMID 18492791.
- PMID 11861619.
- S2CID 25373560.
- PMID 11854195.
- ^ S2CID 30191200.
- ^ PMID 7798218.
- ^ PMID 12388753.
- PMID 29213131.
- PMID 9309390.
- ^ PMID 22560866.
- PMID 20305638.
- ^ S2CID 1267478.
- PMID 25999950.
- PMID 9270830.
- PMID 18550419.
- PMID 10768992.
- S2CID 13336661.
- PMID 22944659.
- ^ Castro-Obregon S (2010). "The Discovery of Lysosomes and Autophagy". Nature Education. 3 (9): 49.
- PMID 24220263.
- PMID 15607973.
- PMID 24336213.
- PMID 23084287.
- ^ Roy CR, Kagan JC (1 January 2013). Evasion of Phagosome Lysosome Fusion and Establishment of a Replicative Organelle by the Intracellular Pathogen Legionella pneumophila. Landes Bioscience.
- PMID 12163465.