Figure 1.

Schematic overview representing the organization of a thyroid follicle. The thyroid follicle lumen displays a protected extracellular compartment which is enclosed by a monolayer of thyroid epithelial cells interconnected by tight junctions. The apical plasma membrane of thyrocytes faces the follicle lumen in which compacted and covalently cross-linked thyroglobulin (Tg) is stored in globules reaching up to 150 μm in diameter. Tg-globules are far too large to be engulfed by single thyrocytes on the whole, thus partial degradation in the extracellular follicle lumen must precede endocytosis. By limited degradation, mediated by cysteine cathepsins within the pericellular space, Tg fragments are liberated and are subsequently endocytosed for degradation in endosomes and lysosomes. Thyroxine liberation by processing of the prohormone Tg starts extracellularly and is continued intracellularly after Tg-fragment internalization. Compartments in which proteolysis of Tg principally takes place are highlighted and the chosen redox- and pH-conditions were used as indicated in the associated boxes (for further details please refer to Background section).