What Is Endosomal Sorting and How Does It Work?

Our cells contain a dynamic network of compartments that functions like a highly organized postal service, receiving, sorting, and dispatching molecular packages. The entry point of this network is the endosome, an organelle that processes materials brought into the cell from the outside. It acts as a cellular entryway where incoming cargo is identified and directed toward its correct destination for reuse or disposal. This internal trafficking system ensures that cells can efficiently manage resources and respond to external signals.

The Endosomal System

The endosomal system is a collection of organelles central to sorting and delivering materials within a cell. Its work begins with endocytosis, a process where the cell membrane folds inward to engulf substances from the outside. This action forms a vesicle, a small membrane-enclosed bubble, that transports its contents into the cell’s interior.

These vesicles then fuse with the first component of the system: the early endosome. Located near the cell’s outer edge, early endosomes serve as the initial receiving station for all incoming traffic. From this first stop, cargo proceeds along different routes.

One destination is the recycling endosome, a tubular network that sends certain materials, like cell surface receptors, back to the plasma membrane for reuse. This pathway allows the cell to maintain the right number of receptors on its surface. Alternatively, cargo marked for disposal is routed toward late endosomes, which are found deeper within the cytoplasm and have an increasingly acidic internal environment.

Endosomal Sorting and Trafficking

The primary function of the endosomal network is the sorting of its contents. When a vesicle delivers cargo to an early endosome, a decision-making process begins, guided by specific molecular tags and sorting machinery that direct the cargo.

A primary signal for a protein to be degraded is a molecular tag called ubiquitin. When a protein is marked with this tag, it is recognized by a series of protein complexes known as the Endosomal Sorting Complexes Required for Transport (ESCRTs). The ESCRT machinery is recruited to the endosomal membrane to identify and gather the ubiquitinated cargo.

The process begins with the ESCRT-0 complex, which recognizes and clusters the tagged proteins. Following this, the other ESCRT complexes—ESCRT-I, -II, and -III—are sequentially assembled.

This assembly causes the endosomal membrane to bend inward, away from the cytoplasm, forming small vesicles within the endosome itself. This creates a structure known as a multivesicular body (MVB), which contains the cargo destined for degradation safely enclosed. This packaging isolates the materials and prepares them for their final journey.

The Final Destinations

Once sorting is complete, cargo is sent to one of two destinations: degradation or recycling. The degradation pathway involves the movement of multivesicular bodies, now considered late endosomes, toward the lysosome, the cell’s waste disposal unit. This journey is guided by the cell’s internal scaffolding, the cytoskeleton.

The fusion of a late endosome with a lysosome is a regulated event mediated by specific proteins on their surfaces. Once they merge, the digestive enzymes of the lysosome, which function in its acidic environment, break down the cargo into basic components that the cell can reuse.

Simultaneously, other materials are routed for reuse through the recycling pathway. Valuable components like the transferrin receptor are directed from the early endosome to the recycling endosome. From this compartment, vesicles travel back to the cell surface, returning the receptors to the plasma membrane where they can begin the cycle anew.

Role in Health and Disease

The endosomal sorting system’s proper function is necessary for cellular health. An example is iron uptake via the transferrin cycle. Iron-carrying transferrin binds to its receptor, is internalized into an early endosome, and releases its iron. The receptor is then sorted to a recycling endosome and returned to the surface. Failures in this process, due to defects in sorting proteins, can impair iron uptake and lead to conditions like anemia.

This pathway is also exploited by pathogens. Many viruses, including influenza and coronaviruses, bind to cell surface receptors and are taken in via endocytosis. For influenza, the late endosome’s acidic environment triggers changes in the virus, allowing it to release its genetic material into the cytoplasm. Some coronaviruses use the pathway by relying on cellular proteases in the endosome to activate their spike proteins for fusion.

Disruptions in endosomal trafficking are also implicated in neurodegenerative disorders like Alzheimer’s disease. An early sign of Alzheimer’s is the swelling of early endosomes in neurons. This dysfunction is linked to the amyloid precursor protein (APP), which can over-activate the protein Rab5, causing endosomes to enlarge. This disrupts the transport of survival signals and contributes to neurodegeneration.