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Defective Thyroglobulin: Cell Biology of Disease
Xiaohan Zhang1, Crystal Young1,2, Yoshiaki Morishita3
1Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI 48105, USA.
Insights
Thyroglobulin misfolding in thyroid follicles causes endoplasmic reticulum stress, leading to thyrocyte cell death. This cellular dysfunction is linked to hypothyroidism and can be studied in cell cultures and animal models.
Area of Science:
- Endocrinology
- Cell Biology
- Molecular Biology
Background:
- Thyroid follicles, composed of thyrocytes, are the functional units of the thyroid gland, surrounding a lumen filled with thyroglobulin (Tg).
- Thyroglobulin is a crucial glycoprotein, essential for thyroid hormone synthesis, and is the most abundant protein in the thyroid gland.
- Genetic variants of thyroglobulin can lead to misfolding, defective endoplasmic reticulum export, hypothyroidism, and thyroidal endoplasmic reticulum stress.
Purpose of the Study:
- To investigate the cellular and pathophysiological consequences of thyroglobulin misfolding and endoplasmic reticulum stress in thyroid cells.
- To explore the susceptibility of thyrocytes to cell death under conditions of chronic endoplasmic reticulum stress induced by defective thyroglobulin.
Main Methods:
- Utilizing thyrocyte cell culture models to study human thyroglobulin variants.
- Employing genetically manipulable animal models, such as mice, to investigate the in vivo effects of thyroglobulin misfolding.
- Combining cell biological and pathophysiological approaches to analyze the consequences of endoplasmic reticulum stress.
Main Results:
- Thyroglobulin misfolding leads to defective protein export from the endoplasmic reticulum.
- Thyrocytes experiencing chronic endoplasmic reticulum stress exhibit increased susceptibility to cell death.
- Thyroglobulin misfolding and subsequent endoplasmic reticulum stress have significant cell biological and pathophysiological implications.
Conclusions:
- Defective thyroglobulin processing and resultant endoplasmic reticulum stress are key contributors to hypothyroidism.
- Thyroid cell death under chronic stress conditions is a critical factor in the pathophysiology of thyroid dysfunction.
- Experimental models provide valuable insights into the mechanisms underlying thyroglobulin-related thyroid diseases.
Abstract:
The primary functional units of the thyroid gland are follicles of various sizes comprised of a monolayer of epithelial cells (thyrocytes) surrounding an apical extracellular cavity known as the follicle lumen. In the normal thyroid gland, the follicle lumen is filled with secreted protein (referred to as colloid), comprised nearly exclusively of thyroglobulin with a half-life ranging from days to weeks. At the cellular boundary of the follicle lumen, secreted thyroglobulin becomes iodinated, resulting from the coordinated activities of enzymes localized to the thyrocyte apical plasma membrane. Thyroglobulin appearance in evolution is essentially synchronous with the appearance of the follicular architecture of the vertebrate thyroid gland. Thyroglobulin is the most highly expressed thyroid gene and represents the most abundantly expressed thyroid protein. Wildtype thyroglobulin protein is a large and complex glycoprotein that folds in the endoplasmic reticulum, leading to homodimerization and export via the classical secretory pathway to the follicle lumen. However, of the hundreds of human thyroglobulin genetic variants, most exhibit increased susceptibility to misfolding with defective export from the endoplasmic reticulum, triggering hypothyroidism as well as thyroidal endoplasmic reticulum stress. The human disease of hypothyroidism with defective thyroglobulin (either homozygous, or compound heterozygous) can be experimentally modeled in thyrocyte cell culture, or in whole animals, such as mice that are readily amenable to genetic manipulation. From a combination of approaches, it can be demonstrated that in the setting of thyroglobulin misfolding, thyrocytes under chronic continuous ER stress exhibit increased susceptibility to cell death, with interesting cell biological and pathophysiological consequences.
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