“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 9 publications

(28 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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Extracellular phase separation mediates storage and release of thyroglobulin in the thyroid follicular lumen

Yao,

Erkamp,

Sneideris

et al. 2024

Preprint

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Thyroid hormones are produced by the thyroid gland and are essential for regulating metabolism, growth and development. Maintenance of circulating thyroid hormone levels within an appropriate range is thus a prerequisite for health. In vivo, this objective is, at least in part, facilitated through an extracellular storage depot of thyroglobulin, the glycoprotein precursor for thyroid hormones, in the thyroid follicular lumen. The molecular basis for how soluble thyroglobulin molecules form such dense depot assemblies remains elusive. Here, we describe in vitro biophysical analysis of thyroglobulin phase behaviour, suggesting that thyroglobulin is prone to undergoing ionic strength-dependent phase separation, leading to the formation of liquid-like condensates. Fluorescence photobleaching measurements further show that these condensates age as a function of time to form reversible gel-like high density storage depots of thyroglobulin. Immunofluorescence experiments on mouse and human thyroid follicles ex vivo reveal that spherical globules of Tg protein dense phase are present in the follicular lumen, consistent with the idea that Tg undergoes phase separation. These findings reveal a molecular mechanism for the last-come-first-served process of thyroglobulin storage and release, suggesting a role for extracellular phase separation in thyroid hormone homeostasis by providing organizational and architectural specificity without requiring membrane-mediated confinement.

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

Cited by 9 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

Extracellular phase separation mediates storage and release of thyroglobulin in the thyroid follicular lumen

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