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Preferential megalin-mediated transcytosis of low-hormonogenic thyroglobulin: A control mechanism for thyroid hormone release

Official URL:https://doi.org/10.1073/pnas.2432267100
PubMed:View item in PubMed
Creators Name:Lisi, S. and Pinchera, A. and McCluskey, R.T. and Willnow, T.E. and Refetoff, S. and Marcocci, C. and Vitti, P. and Menconi, F. and Grasso, L. and Luchetti, F. and Collins, A.B. and Marino, M.
Journal Title:Proceedings of the National Academy of Sciences of the United States of America
Journal Abbreviation:Proc Natl Acad Sci U S A
Volume:100
Number:25
Page Range:14858-14863
Date:1 January 2003
Keywords:Amitrole, Biological Models, Drug Dose-Response Relationship, Endocytosis, Enzyme-Linked Immunosorbent Assay, Graves Disease, Heparitin Sulfate, Homozygote, Hormones, Hypothyroidism, Inbred Lew Rats, LDL-Receptor Related Protein 2, Methimazole, Precipitin Tests, Thyroglobulin, Thyroid Gland, Thyroid Hormones, Transgenic Mice, Animals, Mice, Rats
Abstract:Hormone secretion by thyrocytes occurs by fluid phase uptake and lysosomal degradation of the prohormone thyroglobulin (Tg). However, some Tg internalized by megalin bypasses lysosomes and is transcytosed across cells and released into the bloodstream. Because the hormone content of Tg is variable, we investigated whether this affects transcytosis. We found that rat Tg with a low hormone content [low-hormonogenic rat Tg (low-horm-rTg)] is transcytosed by megalin across thyroid FRTL-5 cells to a greater extent than rat Tg with a high hormone content [hormonogenic rat Tg (horm-rTg)]. In immunoprecipitation experiments, the Tg sequence Arg-2489-Lys-2503 (required for binding to megalin and heparan sulfate proteoglycans) was found to be more exposed in low-horm-rTg, which accounted for its preferential transcytosis. Thus, removal of surface heparan sulfate proteoglycans from FRTL-5 cells or blocking of 2489-2503 reduced transcytosis of low-horm-rTg to a greater extent than that of horm-rTg. Preferential transcytosis of low-horm-rTg affected hormone release. Thus, the increase in hormone release from horm-rTg in FRTL-5 cells determined by megalin blocking (due to reduced transcytosis and enhanced Tg degradation) was rescued by low-horm-rTg, suggesting that megalin is required for effective hormone release. This finding was confirmed in a small number of megalin-deficient mice, which had serological features resembling mild hypothyroidism. Reduced hormone formation within Tg in vivo, due to treatment of rats with aminotriazole or of patients with Graves' disease with methimazole, resulted in increased Tg transcytosis via megalin, in confirmation of results with FRTL-5 cells. Our study points to a major role of megalin in thyroid homeostasis with possible implications in thyroid diseases.
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Item Type:Article

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