Receptor mediated endocytosis:

The bacterial toxin consist of two components: one component (subunit A) which is responsible for the enzymatic activity of the toxin and the other component (subunit B) which is concerned with binding to a specific receptor on the host cell membrane and transferring the enzyme across the membrane. The enzymatic component is not active until it is released from the native (A+B) toxin. Isolated A subunits are enzymatically active but lack binding and cell entry capability. Isolated B subunits may bind to target cells (and even block the binding of the native toxin), but they are nontoxic.

There are two mechanisms of toxin entry into target cells:

1. Direct entry:

The B subunit of the native (A+B) toxin binds to a specific receptor on the target cell and induces the formation of a pore in the membrane through which the A subunit is transferred into the cell cytoplasm.

2. Receptor mediated endocytosis:

Here the native toxin binds to the target cell and the A+B structure is taken into the cell by the process of receptor-mediated endocytosis. The toxin is further internalized in the cell in a membrane-enclosed vesicle called an endosome. H+ ions enter the endosome lowering the internal pH which causes the A+B subunits to separate. The B subunit affects the release of the A subunit from the endosome so that it will reach its target in the cell cytoplasm. The B subunit remains in the endosome and is recycled to the cell surface.

In both cases, a large protein molecule must insert into and cross a membrane lipid bilayer, either the cell membrane or the endosome membrane. This activity is based in the ability of most A+B or A/B toxins, or their B components, to insert into artificial lipid bilayers, creating ion permeable pathways.

Example: Diphtheria Toxin

The diphtheria toxin is produced by Corynebacterium diphtheriae . It is a bacterial exotoxin of the A/B prototype. It has two parts: subunit A, contains the enzymatic activity for inhibition of elongation factor-2 involved in host protein synthesis and subunit B, is responsible for binding to the membrane of a susceptible host cell. The B subunit possesses a region T (translocation) domain which inserts into the endosome membrane thus releasing the enzymatic component into the cytoplasm. In vitro , the native toxin is produced in an inactive form which is activated by the proteolytic enzyme trypsin in the presence of thiol. The diphtheria toxin enters its target cells by either direct entry or receptor mediated endocytosis.