“Thyroglobulin Storage, Processing and Degradation for Thyroid Hormone Liberation”

Brix, Klaudia; Qatato, Maria; Szumska, Joanna; Venugopalan, Vaishnavi; Rehders, Maren

doi:10.1007/978-3-319-72102-6_3

Cited by 6 publications

(25 citation statements)

References 193 publications

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“…4). In this view, the Tgprocessing cysteine cathepsins are restricted in their action by their natural substrate Tg in a self-assisted manner [9,34]. Upon pericellular Tg processing, Tg-intrinsic sequences may become unmasked that act as thyroid-derived peptidase inhibitors (thyropins) [9,34,[52][53][54][55][56].…”

Section: Canonical Tsh Receptor Localization Depends Upon Taar1 Exprementioning

confidence: 99%

“…Moreover, an astonishingly discrete functional autonomy is observed for each and any thyroid follicle within the thyroid gland, which cannot be attributed to canonical TSH regulation of TH generation and release into the blood circulation [9,16,17]. Thus, the TH precursor molecule thyroglobulin (Tg) itself counteracts iodide uptake and thyroid peroxidase (TPO) -mediated iodine organification in thyroid follicles [18].…”

Section: Introductionmentioning

confidence: 99%

“…Alternatively, specific receptors might provide thyroid epithelial cells with means to recycle low iodinated Tg molecules, or deliver intact Tg molecules to the circulation by transcytosis. The different mechanisms that may explain Tg re-internalization, recycling and transcytosis are critically discussed in a recent overview [9], concluding that more research is required to explain their impact on auto-regulation of thyrocytes.…”

Section: Introductionmentioning

confidence: 99%

“…mously (▶Fig. 2), enabling it to operate in an auto-regulatory fashion [9,21]. It is therefore of note that many open questions still remain in uncovering regulation of thyroid cell biology by canonical and non-canonical means.…”

Section: Introductionmentioning

confidence: 99%

“…Here, we will zoom in on the interrelatedness of classical and non-classical pathways of thyroid auto-regulation [9], particularly discussing the G protein-coupled receptors (GPCR) Trace amineassociated receptor 1 (Taar1) and TSH receptor at the apical and basolateral poles of thyrocytes [32,33], respectively, and by explaining how they cross-talk with Tg-processing enzymes [25,34]. Furthermore, we will review specific proposals, namely, (i) Taar1 expression is significant for regulation of thyrocyte function in TH generation [25,33], (ii) Tg-processing is connected to Taar1 function in thyrocytes [25], (iii) Tg-processing is linked to TH transporter-mediated TH release from thyroid follicles [24], (iv) the TH transporter MCT8 interacts on the molecular level with TSH receptors [35], and (v) basolateral TSH receptors and Taar1 at the apical cilia of thyrocytes are co-regulators of thyroid function [25,34].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Auto-Regulation of the Thyroid Gland Beyond Classical Pathways

Brix

Szumska

Weber

et al. 2020

Exp Clin Endocrinol Diabetes

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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.

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Section: Canonical Tsh Receptor Localization Depends Upon Taar1 Exprementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Auto-Regulation of the Thyroid Gland Beyond Classical Pathways

Brix

Szumska

Weber

et al. 2020

Exp Clin Endocrinol Diabetes

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Maintaining the thyroid gland in mutant thyroglobulin–induced hypothyroidism requires thyroid cell proliferation that must continue in adulthood

Zhang

Malik

Young

et al. 2022

Journal of Biological Chemistry

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Lack of L-type amino acid transporter 2 in murine thyroid tissue induces autophagy

Venugopalan

Rehders

Weber

et al. 2023

Journal of Molecular Endocrinology

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Proteolytic cleavage of thyroglobulin (Tg) for thyroid hormone (TH) liberation is followed by TH release from thyroid follicles into the circulation, enabled by TH transporters. The existence of a functional link between Tg-processing cathepsin proteases and TH transporters has been shown to be independent of the hypothalamus-pituitary-thyroid axis. Thus, lack of cathepsin K, combined with genetic defects in the TH transporters Mct8 and Mct10, i.e. the Ctsk‑/-/Mct8-/y/Mct10-/- genotype, results in persistent Tg proteolysis due to autophagy induction. Because amino acid transport by L-type amino acid transporter 2 (Lat2) has been described to regulate autophagy, we asked whether Lat2 availability is affected in Ctsk‑/-/Mct8-/y/Mct10-/- thyroid glands. Our data revealed that while mRNA amounts and sub-cellular localization of Lat2 remained unaltered in thyroid tissue of Ctsk‑/-/Mct8-/y/Mct10-/- mice in comparison to wild-type (WT) controls, the Lat2 protein amounts were significantly reduced. These data suggest a direct link between Lat2 function and autophagy induction in Ctsk‑/-/Mct8-/y/Mct10‑/‑ mice. Indeed, thyroid tissue of Lat2-/- mice showed enhanced endo-lysosomal cathepsin activities, increased autophagosome formation, and enhanced autophagic flux. Collectively, these results suggest a mechanistic link between insufficient Lat2 protein function and autophagy induction in the thyroid gland of male mice.

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“Thyroglobulin Storage, Processing and Degradation for Thyroid Hormone Liberation”

Cited by 6 publications

References 193 publications

Auto-Regulation of the Thyroid Gland Beyond Classical Pathways

Auto-Regulation of the Thyroid Gland Beyond Classical Pathways

Maintaining the thyroid gland in mutant thyroglobulin–induced hypothyroidism requires thyroid cell proliferation that must continue in adulthood

Lack of L-type amino acid transporter 2 in murine thyroid tissue induces autophagy

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