Auto-Regulation of the Thyroid Gland Beyond Classical Pathways

Abstract

This mini-review asks how self-regulation of the thyroid gland is realized at the cellular and molecular levels by canonical and non-canonical means. Canonical pathways of thyroid regulation comprise thyroid stimulating hormone-triggered receptor signaling. As part of non-canonical regulation, we hypothesized an interplay between protease-mediated thyroglobulin processing and thyroid hormone release into the circulation by means of thyroid hormone transporters like Mct8. We proposed a sensing mechanism by different thyroid hormone transporters, present in specific subcellular locations of thyroid epithelial cells, selectively monitoring individual steps of thyroglobulin processing, and thus, the cellular thyroid hormone status. Indeed, we found that proteases and thyroid hormone transporters are functionally inter-connected, however, in a counter-intuitive manner fostering self-thyrotoxicity in particular in Mct8- and/or Mct10-deficient mice. Furthermore, the possible role of the G protein-coupled receptor Taar1 is discussed, because we detected Taar1 at cilia of the apical plasma membrane of thyrocytes in vitro and in situ. Eventually, through pheno-typing Taar1-deficient mice, we identified a co-regulatory role of Taar1 and the thyroid stimulating hormone receptors. Recently, we showed that inhibition of thyroglobulin-processing enzymes results in disappearance of cilia from the apical pole of thyrocytes, while Taar1 is re-located to the endoplasmic reticulum. This pathway features a connection between thyrotropin-stimulated secretion of proteases into the thyroid follicle lumen and substrate-mediated self-assisted control of initially peri-cellular thyroglobulin processing, before its reinternalization by endocytosis, followed by extensive endo-lysosomal liberation of thyroid hormones, which are then released from thyroid follicles by means of thyroid hormone transporters.

The Thyroid Hormone Transporter Mct8 Restricts Cathepsin-Mediated Thyroglobulin Processing in Male Mice through Thyroid Auto-Regulatory Mechanisms That Encompass Autophagy

“…Auto-regulatory mechanisms are important in coping with minor disturbances in thyroid gland function to maintain normal serum TH concentrations, thereby keeping up with TH demands of target organs. Cathepsins are essential for TH liberation prior to TH release from thyroid follicles into the blood circulation [ 3 , 9 ]. There is evidence that the lack of one cathepsins can be functionally compensated by the upregulation of a related cysteine cathepsin [ 19 , 20 ].…”

“…Proteolysis of human and mouse Tg is mediated by cysteine cathepsins B, K, L, and S as well as aspartic cathepsin D [ 20 , 47 , 48 , 49 , 50 ]. Considering the importance of TH for proper functioning of central and peripheral target tissues as well as for the thyroid gland itself, it is both relevant and timely to better understand regulatory mechanisms that control the degree of proteolytic degradation of the precursor molecule Tg for subsequent TH liberation (for a perspective review, see [ 9 ]).…”

“…Solubilization of Tg occurs from the intraluminally stored cross-linked multimeric forms before and upon endocytic reuptake, respectively, and results in subsequent Tg degradation for TH liberation [ 3 , 9 , 50 ]. Previously, we reported that cathepsins B and L are mainly responsible for the solubilization of Tg from its cross-linked forms [ 20 ].…”

“…In response to TSH stimulation, specific proteolytic enzymes called cysteine cathepsins are transported from endo-lysosomes of thyrocytes to the apical plasma membrane and are secreted into the extracellular space, where they exert their proteolytic functions for the solubilization of luminal Tg [ 3 , 7 , 8 ]. Partially solubilized Tg molecules are re-internalized by the thyrocytes, where they are further degraded, within endo-lysosomal compartments, to liberate TH, i.e., 3,3′,5,5′ tetraiodo-L-thyronine (T4) and the biologically active form 3′,3,5 triiodothyronine (T3) [ 9 ]. TH are released into the blood circulation by means of thyroid hormone transmembrane transporters such as monocarboxylate transporters Mct8 and Mct10/TAT1, which also mediate the uptake of TH in peripheral organs [ 10 , 11 , 12 , 13 , 14 ].…”

“…TH are released into the blood circulation by means of thyroid hormone transmembrane transporters such as monocarboxylate transporters Mct8 and Mct10/TAT1, which also mediate the uptake of TH in peripheral organs [ 10 , 11 , 12 , 13 , 14 ]. Tissues dependent on TH include the cardiovascular system, the central nervous system, the intestine, the liver, the skeleton, and the thyroid gland itself, thereby specifying the thyroid gland as a TH releasing as well as TH responding organ [ 9 ]. Thyroid dysfunction arising from disturbed TH generation, TH release, or TH action poses as the most common form of endocrine diseases [ 15 , 16 ].…”