Endocytosis- Definition, Process and Types with Examples

Endocytosis is a cellular mechanism for internalizing substances from the external environment. It allows the cell to take up molecules that are too large or polar to cross the cell membrane by diffusion or transporters. Endocytosis also enables the cell to regulate its membrane composition, receptor signaling, and nutrient uptake.

Endocytosis involves the formation of membrane-bound vesicles that pinch off from the cell membrane and deliver their contents to various intracellular compartments, such as endosomes, lysosomes, or the Golgi apparatus. The vesicles can be formed by different mechanisms depending on the type and size of the substance being internalized, as well as the specific function of the endocytic pathway.

Endocytosis is essential for many biological processes, such as immune response, cell signaling, development, and homeostasis. Endocytosis also plays a role in some pathological conditions, such as viral infection, cancer, and neurodegeneration. In this article, we will summarize the process of endocytosis and its three main types: phagocytosis, pinocytosis, and receptor-mediated endocytosis. We will also provide some examples of how endocytosis is involved in various cellular functions and phenomena.

Endocytosis is a cellular process in which substances are brought into the cell by engulfing them with the cell membrane. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. Endocytosis can be used to transport molecules that cannot pass through the membrane passively, such as macromolecules, nutrients, pathogens, and cell surface receptors .

There are different types of endocytosis mechanisms that vary in the size, shape, and composition of the vesicles and the molecules they transport . These include:

• Phagocytosis: Also known as cell eating; this is the process whereby the cell membrane of a cell extends toward a particle, engulfing it and enclosing it within a vesicle called a phagosome . Phagocytosis is mainly used by immune cells to eliminate pathogens and foreign matter from the body .
• Pinocytosis: Also known as cell drinking or fluid endocytosis; this is a form of endocytosis where small particles in extracellular fluids enter the cell through the cell membrane by invagination forming a small vesicle called a pinocytic vesicle . Pinocytosis is mainly used by cells to absorb nutrients and fluids from the environment .
• Receptor-mediated endocytosis: This is a type of endocytosis that involves the internalization and recycling of receptors that are used in processes such as signal transduction and nutrient uptake . Receptor-mediated endocytosis is initiated by the binding of specific molecules (ligands) to their corresponding receptors on the cell membrane . The receptor-ligand complexes then cluster together and form coated pits that invaginate and pinch off to form coated vesicles . The most common type of receptor-mediated endocytosis is clathrin-mediated endocytosis, which uses a protein called clathrin to form the coated pits and vesicles .

The vesicles formed by endocytosis then undergo further processing by the cell. They can fuse with other vesicles or organelles, such as endosomes or lysosomes, where they are sorted, digested, or recycled . The products of endocytosis can then be used by the cell for various functions, such as metabolism, signaling, growth, or defense .

Endocytosis is an essential process for all cells to maintain homeostasis and adapt to changing environmental conditions. It allows cells to regulate their membrane composition, communicate with other cells, acquire nutrients and energy, and remove unwanted or harmful substances .

Endocytosis is a cellular process that allows cells to take in substances from the external environment by forming vesicles from the plasma membrane. There are three main types of endocytosis mechanisms: phagocytosis, pinocytosis, and receptor-mediated endocytosis . Each type has a different way of recognizing and internalizing specific molecules or particles.

Phagocytosis

Phagocytosis, also known as "cell eating", is the intake of large solid material or food particles by specialized cells called phagocytes . Phagocytes extend their membrane projections called pseudopodia to surround and engulf the target particle, forming a vesicle called a phagosome. The phagosome then fuses with lysosomes, which contain digestive enzymes that break down the ingested material. The degraded products are either released by exocytosis or used by the cell . Phagocytosis is an important mechanism for the immune system to eliminate pathogens and cell debris .

Pinocytosis

Pinocytosis, also known as "cell drinking", is the intake of small particles in extracellular fluid by forming small vesicles from the plasma membrane . Pinocytosis does not require specific receptors or ligands, but rather occurs randomly along the cell surface . The pinocytic vesicles then fuse with endosomes, which sort and deliver the ingested molecules to different destinations within the cell . Pinocytosis is a common way for cells to absorb nutrients and fluids from their surroundings .

Receptor-mediated endocytosis

Receptor-mediated endocytosis, also known as clathrin-mediated endocytosis, is the selective uptake of molecules that bind to specific receptors on the cell surface . The receptor-ligand complexes cluster in regions of the plasma membrane that are coated with a protein called clathrin, which helps to shape and stabilize the forming vesicles . The clathrin-coated vesicles then pinch off from the membrane and lose their clathrin coat. The uncoated vesicles fuse with endosomes, which separate the receptors from the ligands and recycle them back to the plasma membrane or to other organelles . Receptor-mediated endocytosis is a highly efficient and specific way for cells to internalize molecules that are involved in processes such as signal transduction and nutrient uptake .

Phagocytosis is a type of endocytosis that involves the engulfment of large particles (≥ 0.5 μm) by a cell, forming an internal compartment called a phagosome. A cell that performs phagocytosis is called a phagocyte. Phagocytosis is a major mechanism of the innate immune system, as well as a way for some single-celled organisms to obtain nutrients.

Phagocytosis takes place in five steps:

1. Detection and attachment: The phagocyte detects the particle of interest or an antigen and moves towards it. The phagocyte then attaches itself to the target particle or antigen. Phagocytes have the ability to extend their membrane (pseudopodia) to the target particle and surround it. The pseudopodia extend toward each other while enclosing the particle.
2. Formation of phagosome: The particle is then enclosed within the vesicle formed from the extended pseudopodia that have fused. The vesicle with the enclosed particle is known as a phagosome. This is the vesicle that is digested by the phagocyte.
3. Fusion with lysosomes: The phagosome fuses with the lysosomes of the phagocyte forming a phagolysosome. The lysosomes have digestive enzymes that degrade or digest the materials contained in the vesicle.
4. Degradation of particle: The enzymes in the phagolysosome break down the particle into smaller molecules that can be used by the cell or released into the extracellular environment.
5. Expulsion of degraded particles: The degraded particles are then expelled from the phagocytic cell by exocytosis.

The following diagram illustrates the process of phagocytosis:

 Particle
|
v
_________
| | Pseudopodia
| |<----------------
| | |
|| |
| |
v v
_________ _________
| | | |
| Phagocyte| | Phagocyte|
|| ||
| |
v v
_________ _________
| | | |
| Phagosome| |Phagolysosome|
|| ||
| |
v v
_________ _________
| | | |
| Lysosome| | Degraded |
|| | particles|
^ |
| v
_________ _________
| | | |
| Phagocyte|<----------| Phagocyte|
|| Exocytosis||

Phagocytosis is a type of endocytosis that involves the engulfment of large particles (such as bacteria, viruses, or dead cells) by specialized cells called phagocytes. Phagocytes are part of the immune system and they help to eliminate pathogens and cell debris from the body. Some of the main types of phagocytes are neutrophils, macrophages, dendritic cells, and B lymphocytes.

One of the most common examples of phagocytosis is the mechanism of immune cells such as macrophages, dendritic cells, and neutrophils. These cells patrol the tissues and blood vessels and detect foreign or harmful particles by using various receptors on their surface. These receptors can bind to molecules that are produced by bacteria, such as lipopolysaccharide (LPS), peptidoglycan, or flagellin, or to molecules that are coated with antibodies or complement proteins by the immune system. These molecules act as opsonins, which enhance the attachment of phagocytes to their targets.

Once a phagocyte recognizes and binds to a particle, it extends its plasma membrane around it and forms a vesicle called a phagosome. The phagosome then fuses with a lysosome, which is an organelle that contains digestive enzymes and acidic pH. The fusion results in a phagolysosome, where the particle is degraded into smaller components that can be recycled or expelled by the cell. Some of the degraded components can also be presented on the surface of the phagocyte by using major histocompatibility complex (MHC) molecules. This allows the phagocyte to communicate with other immune cells, such as T lymphocytes, and activate an adaptive immune response.

The following steps summarize the process of phagocytosis by immune cells:

1. Detection: The phagocyte detects a foreign or harmful particle by using its receptors.
2. Attachment: The phagocyte attaches itself to the particle by using opsonins or direct binding.
3. Engulfment: The phagocyte extends its membrane around the particle and forms a phagosome.
4. Digestion: The phagosome fuses with a lysosome and forms a phagolysosome, where the particle is digested by enzymes and acid.
5. Expulsion: The digested components are either recycled or expelled by the cell by exocytosis.
6. Presentation: Some of the digested components are presented on the surface of the cell by MHC molecules for recognition by other immune cells.

 _________
/ \ Particle
| Phagocyte| /
\/ /
| /
| /
| / Phagosome
| / /
V V V
_________
/ \ Lysosome
| Phagocyte| /
\/ /
| /
| /
| / Phagolysosome
| / /
V V V
_________
/ \ Digested components
| Phagocyte| /
\/ /
| /
| /
| / Exocytosis
| / /
V V V
_________
/ \ MHC presentation
| Phagocyte| /
\/--/

Phagocytosis is an essential mechanism for the innate immunity and also for the initiation of adaptive immunity. It helps to clear infections, inflammation, and tissue damage by removing pathogens and cell debris. It also helps to regulate immune responses by presenting antigens to other immune cells and producing cytokines that modulate inflammation and immunity.

Pinocytosis is a form of endocytosis that involves the uptake of extracellular fluids and dissolved solutes, such as fat droplets, vitamins, and antigens. The term pinocytosis is derived from the Greek word "pino", meaning "to drink", and "cyto", meaning "cell". Therefore, the process of pinocytosis can be thought of as cellular drinking.

Pinocytosis occurs in several steps and typically starts with positively charged molecules, such as a peptide or protein, interacting with the negatively charged cell membrane. Once they come into close contact, the particles bind to the cell membrane, thereby changing the cell membrane`s shape to create a pouch that surrounds the particle. As the cell plasma membrane curls around on itself, or invaginates, it brings extracellular fluid along with the particle(s) into the cell. Since the solutes are being moved against their concentration gradient, energy in the form of ATP is required for this process.

The invaginated pouch then pinches off from the cell membrane, forming a small vesicle called a pinosome or pinocytic vesicle. The pinosome has a diameter of about 100 to 200 nanometers and requires an electron microscope for visualization. The pinosome then fuses with an endosome, a membrane-bound organelle that sorts and transports materials within the cell. The endosome may either recycle the pinosome back to the cell membrane or deliver it to a lysosome, another membrane-bound organelle that contains digestive enzymes. The lysosome breaks down the contents of the pinosome and releases them into the cytoplasm for utilization by the cell.

Pinocytosis is a non-specific process that does not require specific receptors on the cell membrane to recognize and bind to the solutes. Therefore, pinocytosis can take up any fluid or solute that is present in the extracellular environment. However, some cells may regulate pinocytosis by controlling the rate and extent of membrane invagination and vesicle formation.

Pinocytosis is a common mechanism for cells to absorb nutrients, fluids, and antigens from their surroundings. Pinocytosis also plays a role in immune system function by allowing some immune cells to sample antigens from extracellular fluids and present them to other immune cells for recognition and activation.

Receptor-mediated endocytosis is a type of endocytosis that involves the specific uptake of molecules that bind to receptors on the cell membrane. Unlike phagocytosis and pinocytosis, which are non-selective and can engulf any particles in the extracellular fluid, receptor-mediated endocytosis only internalizes the molecules that are recognized by the receptors. This allows the cell to regulate the intake of certain substances, such as hormones, growth factors, nutrients, and viruses.

Receptor-mediated endocytosis is also known as clathrin-mediated endocytosis because it involves the formation of clathrin-coated vesicles. Clathrin is a protein that forms a lattice-like structure around the vesicle and helps to shape and stabilize it. The process of receptor-mediated endocytosis can be summarized as follows:

• The molecules that need to be internalized (ligands) bind to their specific receptors on the cell membrane. The receptors are usually transmembrane proteins that have an extracellular domain for ligand binding and an intracellular domain for interacting with other proteins.
• The ligand-receptor complexes cluster together and recruit adaptor proteins that bind to both the receptors and clathrin. The adaptor proteins also interact with phosphatidylinositol-4,5-bisphosphate (PIP2), a lipid molecule that accumulates on the inner leaflet of the membrane.
• The accumulation of PIP2, adaptor proteins, and clathrin causes the membrane to bend inward and form a pit. The pit deepens and eventually pinches off from the membrane with the help of a protein called dynamin, which wraps around the neck of the vesicle and constricts it.
• The resulting clathrin-coated vesicle contains the ligand-receptor complexes and some extracellular fluid. The vesicle then detaches from the clathrin coat and fuses with an early endosome, a sorting compartment that receives incoming vesicles.
• In the early endosome, the ligands and receptors are separated by changes in pH and other factors. The ligands are either degraded in lysosomes or recycled back to the cell membrane or other organelles. The receptors are either recycled back to the cell membrane or sent to late endosomes for further sorting.

Receptor-mediated endocytosis is an important mechanism for regulating cellular functions and signaling pathways. For example, it allows cells to take up cholesterol from low-density lipoproteins (LDL), iron from transferrin, growth factors from extracellular matrix, and hormones from blood circulation. It also enables cells to remove activated receptors from the cell surface and terminate their signaling effects. Moreover, it can mediate the entry of some viruses into host cells by exploiting their receptor-ligand interactions.

Clathrin-coated pits are the sites where clathrin-mediated endocytosis begins. They are invaginations of the plasma membrane that are coated with a lattice of clathrin and other proteins. Clathrin-coated pits form by the following steps:

• Accumulation of PIP2: Phosphatidylinositol-4,5-bisphosphate (PIP2) is a phospholipid that is enriched in the inner leaflet of the plasma membrane. PIP2 is synthesized by the enzyme phosphatidylinositol 4-phosphate 5-kinase (PIP5K), which catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PIP) to PIP2. PIP2 accumulation is stimulated by various signals, such as growth factors, hormones, and neurotransmitters, that activate receptors on the cell surface. PIP2 serves as a docking site for many endocytic proteins that bind to its negatively charged head group.

• Recruitment of adaptor proteins: Adaptor proteins (APs) are a family of proteins that link clathrin to cargo molecules and to the plasma membrane. There are four major types of APs: AP1, AP2, AP3, and AP4. AP2 is the most abundant and important adaptor protein for clathrin-mediated endocytosis at the plasma membrane. AP2 consists of four subunits: alpha, beta2, mu2, and sigma2. AP2 binds to PIP2 through its alpha and beta2 subunits, and to cargo molecules through its mu2 and sigma2 subunits. The mu2 subunit recognizes specific motifs on the cytoplasmic tails of transmembrane receptors, such as tyrosine-based YXXØ or dileucine-based XXXL motifs, where X is any amino acid and Ø is a bulky hydrophobic residue. The sigma2 subunit recognizes motifs that contain acidic residues, such as XXX.

• Attachment of clathrin: Clathrin is a cytosolic protein that forms a triskelion-shaped structure composed of three heavy chains and three light chains. Clathrin triskelia can self-assemble into a polygonal lattice that coats the vesicle bud. Clathrin binds to AP2 through its terminal domains, which interact with the beta2 and mu2 subunits of AP2. Clathrin also binds to other proteins that facilitate its assembly and disassembly, such as epsin, amphiphysin, and auxilin.

• Invagination of the membrane: The clathrin coat induces curvature on the plasma membrane by forming a cage-like structure around the vesicle bud. The curvature is also aided by other proteins that deform the membrane by inserting amphipathic helices or BAR domains into the lipid bilayer, such as epsin, amphiphysin, endophilin, and syndapin. These proteins also recruit dynamin, a GTPase that constricts the neck of the vesicle bud.

• Scission of the vesicle: The final step of clathrin-coated pit formation is the detachment of the vesicle from the plasma membrane by a fission event. This requires the hydrolysis of GTP by dynamin, which generates mechanical force to squeeze and sever the membrane neck. Dynamin also interacts with other proteins that facilitate membrane scission, such as endophilin, syndapin, SNX9, and BIN1.

The resulting clathrin-coated vesicle then uncoats by shedding its clathrin lattice and adaptor proteins, which are recycled back to the cytosol or the plasma membrane. The uncoated vesicle then fuses with an early endosome, where its cargo is sorted for degradation or recycling.

Clathrin-mediated endocytosis is a specific type of receptor-mediated endocytosis that involves the internalization of receptors and their ligands by forming clathrin-coated vesicles at the plasma membrane. This process is important for various cellular functions, such as nutrient uptake, signal transduction, synaptic transmission and membrane recycling. Here are some examples of clathrin-mediated endocytosis in different biological contexts:

• Iron-bound transferrin recycling: Transferrin is a protein that binds iron in the blood and delivers it to cells. Transferrin receptors are expressed on the cell surface and bind transferrin with high affinity. The transferrin-receptor complex is then internalized by clathrin-mediated endocytosis and transported to early endosomes. In the acidic environment of the endosome, iron is released from transferrin and transported to the cytoplasm or stored in ferritin. The transferrin-receptor complex then recycles back to the plasma membrane by either returning to the same clathrin-coated pit or by transferring to another one . This process allows cells to regulate their iron uptake and avoid iron overload or deficiency.

• Uptake of cholesterol bound to low-density lipoprotein (LDL): LDL is a complex of phospholipid, protein and cholesterol that carries cholesterol from the liver to peripheral tissues. LDL receptors are expressed on the cell surface and bind LDL with high affinity. The LDL-receptor complex is then internalized by clathrin-mediated endocytosis and transported to late endosomes or lysosomes. In the lysosome, LDL is degraded by hydrolytic enzymes and cholesterol is released into the cytoplasm. Cholesterol can then be used for membrane synthesis, steroid hormone production or stored in lipid droplets . This process allows cells to regulate their cholesterol levels and avoid atherosclerosis or other diseases.

• Viral entry: Many types of viruses use clathrin-mediated endocytosis to enter the cell, including dengue virus, hepatitis C virus, reoviruses and others . Viruses bind to specific receptors on the cell surface and trigger the formation of clathrin-coated pits. The virus-receptor complex is then internalized by clathrin-mediated endocytosis and transported to endosomes. Depending on the virus, different factors such as pH, proteases or fusion proteins mediate the release of viral genome or capsid into the cytoplasm. This process allows viruses to exploit the cellular machinery for infection and replication.

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