Shiga toxin is a protein poison created by bacteria such as Shigella dysenteriae and specific strains of Escherichia coli. The severe illness associated with these infections is a direct result of the toxin’s activity within the body, not the bacteria themselves. This substance is highly efficient at disrupting cellular function, leading to a cascade of damaging effects. Its ability to target and destroy specific cells makes it a significant cause of foodborne illness.
The Toxin’s Molecular Blueprint
The Shiga toxin’s structure is often described as an A-B toxin. It is composed of two main parts: a single A-subunit and a ring of five B-subunits. The B-subunits form the delivery system, a pentameric ring that identifies and attaches to the surface of a target cell. The A-subunit is the toxin’s active component, the “warhead” that carries out the destructive work, but it remains inert until it is inside the cell. The A-subunit is further divided into an A1 fragment, the enzymatically active part, and an A2 fragment that connects it to the B-ring.
Gaining Cellular Access
The journey of the Shiga toxin into a cell begins with a specific interaction. The five B-subunits of the toxin recognize and bind to a molecule on the cell surface called globotriaosylceramide, or Gb3. Cells that have a high density of Gb3 receptors on their membrane are the primary targets for the toxin. This binding is the first step in the toxin’s invasion.
Once attached, the cell is tricked into pulling the toxin inside. The cell membrane folds inward, enveloping the bound toxin in a process known as receptor-mediated endocytosis. This results in the toxin being enclosed within a membrane-bound bubble called an endosome. From the endosome, the toxin begins a journey deeper into the cell’s interior.
Internal Sabotage of the Cell
Once inside an endosome, the Shiga toxin is not sent to lysosomes for degradation. Instead, it undertakes a retrograde journey, moving backward through the cell’s transport pathways. The toxin travels from the endosome to the Golgi apparatus, and then to the endoplasmic reticulum (ER), the cell’s protein production factory. This hijacking of the cell’s internal mail system is an effective evasion tactic.
Within the endoplasmic reticulum, the toxin’s A-subunit is prepared for action. A cellular enzyme cleaves the A-subunit, separating the active A1 fragment from the A2 fragment. This cleavage activates the A1 fragment, which is then released from the ER into the cytoplasm, the fluid-filled space where the protein-making machinery resides.
Now free in the cytoplasm, the A1 fragment targets the cell’s ribosomes—the machines responsible for building proteins. It functions as a specific enzyme, seeking out the large 60S subunit of the ribosome. It then performs a precise chemical modification, removing one specific adenine base (A4324) from the 28S ribosomal RNA. This single alteration is irreversible and renders the ribosome non-functional, permanently halting protein synthesis.
Consequences of Cellular Destruction
The shutdown of protein synthesis leads to the death of the cell, and the location of these dying cells determines the symptoms. The cells most vulnerable to Shiga toxin are those with the highest concentration of Gb3 receptors. These are primarily the endothelial cells that line the small blood vessels, especially those in the intestines and the kidneys.
In the gut, the widespread death of these endothelial cells causes the walls of the small blood vessels to break down. This damage leads to bleeding into the intestines, resulting in the severe, bloody diarrhea known as hemorrhagic colitis. The destruction of the intestinal lining is a direct consequence of the toxin’s action.
When the toxin enters the bloodstream, it circulates and reaches the kidneys, which are rich in Gb3-expressing cells. The damage to the small blood vessels in the kidneys is particularly severe and can lead to a life-threatening condition called Hemolytic Uremic Syndrome (HUS). HUS is defined by a trio of symptoms: acute kidney failure due to vessel damage, anemia from the destruction of red blood cells in these damaged vessels, and a low platelet count as platelets are consumed in attempts to form clots.