{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T18:43:42Z","timestamp":1786992222566,"version":"build-2736575974"},"reference-count":100,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,11,6]],"date-time":"2022-11-06T00:00:00Z","timestamp":1667692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK132017"],"award-info":[{"award-number":["R01 DK132017"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms232113605","type":"journal-article","created":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T10:53:06Z","timestamp":1667904786000},"page":"13605","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Defective Thyroglobulin: Cell Biology of Disease"],"prefix":"10.3390","volume":"23","author":[{"given":"Xiaohan","family":"Zhang","sequence":"first","affiliation":[{"name":"Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Young","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiaki","family":"Morishita","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Department of Internal Medicine, Aichi Medical University, Nagakute 480-1195, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kookjoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omer O.","family":"Kabil","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Department of Natural Sciences, Lindenwood University, Saint Charles, MO 63301, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver B.","family":"Clarke","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Di Jeso","sequence":"additional","affiliation":[{"name":"Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4007-8799","authenticated-orcid":false,"given":"Peter","family":"Arvan","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1242\/jcs.089110","article-title":"Protein localization in disease and therapy","volume":"124","author":"Hung","year":"2011","journal-title":"J. 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