Role of Multimerized Porcine Thyroglobulin in Iodine Storage

Baudry, Nathalie; Lejeune, Pierre-Jean; Delom, Frédéric; Vinet, Liliane; Carayon, Pierre; Mallet, Bernard

doi:10.1006/bbrc.1997.7952

Cited by 22 publications

(14 citation statements)

References 19 publications

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“…Human Tg globules consist of Tg mainly cross-linked by disulfide bridges (4,5). In addition to disulfide cross-links, isodipeptide bonds were detected in bovine (3,6), and dityrosine links in porcine Tg globules (31). Here, we have observed the occurrence of multilayered Tg in mouse thyroids, indicating that covalently cross-linked Tg exists also in the lumen of mouse thyroid follicles (Figure 8).…”

Section: Solubilization Of Luminal Tg Depends On Expression Of Cathepsupporting

confidence: 52%

Thyroid functions of mouse cathepsins B, K, and L

Friedrichs¹,

Tepel²,

Reinheckel³

et al. 2003

J. Clin. Invest.

196

137

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Section: Solubilization Of Luminal Tg Depends On Expression Of Cathepsupporting

confidence: 52%

Thyroid functions of mouse cathepsins B, K, and L

Friedrichs¹,

Tepel²,

Reinheckel³

et al. 2003

J. Clin. Invest.

196

137

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“…The largest Tg-aggregates found in the thyroid gland are represented by the so-called thyroid globules, which consist of up to 800 mg Tg per ml in supra-molecular arrangements that are made of covalently cross-linked Tg molecules. Intra-and intermolecular cross-linking of Tg depends on species-specific molecular mechanisms including disulfide bond formation, dityrosine bonding and transglutaminase-mediated isopeptide cross-links [11,[16][17][18][19][20]. Thus, the task of proteolytic processing of Tg can be compared with that of some other well-known and physiologically important cathepsin K substrates, namely collagen I and elastin of the extracellular matrix (see Fig.…”

Section: Thyroid-specific Functions Of Cysteine Cathepsins In Thyroglmentioning

confidence: 99%

Thyroid Cathepsin K: Roles in Physiology and Thyroid Disease

Dauth

Arampatzidou

Rehders

et al. 2011

Clinic Rev Bone Miner Metab

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The human genome encodes 11 cysteine cathepsins belonging to the papain-like family of cysteine peptidases that are known predominantly as endo-lysosomal enzymes. However, it is now understood that the functions and activities of cysteine cathepsins are not limited to endo-lysosomal compartments, as they are also active in the peri-and extracellular space. The thyroid gland is an endocrine organ where such intra-and extracellular proteolytic activities are required to solubilize the prohormone thyroglobulin from its luminal, covalently cross-linked storage forms for subsequent processing into smaller protein fragments and thyroid hormone liberation. Cathepsin K has been identified as one of the cysteine cathepsins with a crucial role in thyroglobulin processing. However, cathepsin K has mainly been a key focus of attention in the last few years because of its high expression in osteoclasts and due to its essential role as collagenase and elastase important for bone remodelling. Besides its remarkable function as an endopeptidase acting on highmolecular mass, covalently cross-linked extracellular substrates such as type I collagen, elastin or thyroglobulin, cathepsin K is also one of the very few proteolytic enzymes that is able to directly liberate thyroxine from thyroglobulin fragments by exopeptidase action. Thus, thyroid cathepsin K is now accepted as a cysteine peptidase with a vital role in liberation of thyroid hormones, which in turn are essential for homoeostasis by triggering a number of important biological processes, ranging from growth and brain development in young vertebrates to tissue remodelling events during morphogenesis or wound healing, as well as control of metabolic pathways and thermoregulation in adults. This review focuses on thyroid cathepsin K and will discuss how localization and trafficking within thyroid epithelial cells explain its thyroid-specific functions. The effects of targeted cathepsin K gene ablation will be summarized from the perspective of the thyroid gland, and we will propose potential consequences of short-and long-term inhibition of thyroid cathepsin K activity for the main thyroid hormone target tissues, namely bone, cardiovascular and immune systems, intestine, and the central nervous system, in addition to the thyroid gland itself.

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“…Tg aggregates differ from soluble Tg multimers in that they contains about 40% more iodine but almost no hormone (8). In addition, Tg aggregates are formed by several types of covalent cross-links: disulfide, dityrosine, and ␥-glutamyl-lysine bridges (7)(8)(9)(10). The process of di-, tri-, and multimerization of Tg19S is also observed in vitro as the result of iodination and coupling.…”

mentioning

confidence: 99%

Role of Extracellular Molecular Chaperones in the Folding of Oxidized Proteins

Delom

Mallet²,

Carayon

et al. 2001

Journal of Biological Chemistry

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The process of thyroid hormone synthesis, which occurs in the lumen of the thyroid follicles, results from an oxidative reaction leading, as side effects, to the multimerization of thyroglobulin (TG), the prothyroid hormone. Although hormone synthesis is a continuous process, the amount of Tg multimers is relatively constant. Here, we investigated the role of two molecular chaperones, protein disulfide isomerase (PDI) and immunoglobulin heavy chain-binding protein (BiP), present in the follicular lumen, on the multimerization process due to oxidation using both native Tg and its N-terminal domain (NTD). In vitro, PDI decreased multimerization of Tg and even suppressed the formation of NTD multimers. Under the same conditions, BiP was able to bind to Tg and NTD multimers but did not affect the process of multimerization. Associating BiP with PDI did not enhance the ability of PDI to limit the formation of multimers produced by oxidation. However, when BiP and PDI were reacted together with the multimeric forms and for a longer time (48 h), BiP greatly increased the efficiency of PDI. Accordingly, these two molecular chaperones probably act sequentially on the reduction of the intermolecular disulfide bridges. In the thyroid, a similar process may also be effective and participate in limiting the amount of Tg multimers present in the colloid. These results suggest that extracellular molecular chaperones play a similar role to that occurring in the endoplasmic reticulum and, furthermore, take part in the control of multimerization and aggregation of proteins formed by oxidation.

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Role of Multimerized Porcine Thyroglobulin in Iodine Storage

Cited by 22 publications

References 19 publications

Thyroid functions of mouse cathepsins B, K, and L

Thyroid functions of mouse cathepsins B, K, and L

Thyroid Cathepsin K: Roles in Physiology and Thyroid Disease

Role of Extracellular Molecular Chaperones in the Folding of Oxidized Proteins

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