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Thyroid hormone (TH) target cells need to adopt mechanisms to maintain sufficient levels of TH to ensure regular functions. This includes thyroid epithelial cells, which generate TH in addition to being TH-responsive. However, the cellular and molecular pathways underlying thyroid auto-regulation are insufficiently understood. In order to investigate whether thyroglobulin processing and TH export are sensed by thyrocytes, we inactivated thyroglobulin-processing cathepsins and TH-exporting monocarboxylate transporters (Mct) in the mouse. The states of thyroglobulin storage and its protease-mediated processing and degradation were related to the levels of TH transporter molecules by immunoblotting and immunofluorescence microscopy. Thyroid epithelial cells of cathepsin-deficient mice showed increased Mct8 protein levels at the basolateral plasma membrane domains when compared to wild type controls. While the protein amounts of the thyroglobulin-degrading cathepsin D remained largely unaffected by Mct8 or Mct10 single-deficiencies, a significant increase in the amounts of the thyroglobulin-processing cathepsins B and L was detectable in particular in Mct8/Mct10 double deficiency. In addition, it was observed that larger endo-lysosomes containing cathepsins B, D, and L were typical for Mct8- and/or Mct10-deficient mouse thyroid epithelial cells. These data support the notion of a crosstalk between TH transporters and thyroglobulin-processing proteases in thyroid epithelial cells. We conclude that a defect in exporting thyroxine from thyroid follicles feeds back positively on its cathepsin-mediated proteolytic liberation from the precursor thyroglobulin, thereby adding to the development of auto-thyrotoxic states in Mct8 and/or Mct10 deficiencies. The data suggest TH sensing molecules within thyrocytes that contribute to thyroid auto-regulation. [ABSTRACT FROM AUTHOR]