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J Biol Chem, Vol. 275, Issue 10, 7125-7137, March 10, 2000
From the When thyroglobulin (Tg) is
endocytosed by thyrocytes and transported to lysosomes, thyroid
hormones (T4 and T3) are released. However, some internalized Tg is
transcytosed intact into the bloodstream, thereby avoiding proteolytic
cleavage. Here we show that megalin (gp330), a Tg receptor on thyroid
cells, plays a role in Tg transcytosis. Following incubation with
exogenous rat Tg at 37 °C, Fisher rat thyroid (FRTL-5) cells, a
differentiated thyroid cell line, released T3 into the medium. However,
when cells were incubated with Tg plus either of two megalin
competitors, T3 release was increased, suggesting that Tg internalized
by megalin bypassed the lysosomal pathway, possibly with release of
undegraded Tg from cells. To assess this possibility, we performed
experiments in which FRTL-5 cells were incubated with either unlabeled
or 125I-labeled Tg at 37 °C to allow
internalization, treated with heparin to remove cell surface-bound Tg,
and further incubated at 37 °C to allow Tg release. Intact 330-kDa
Tg was released into the medium, and the amount released was markedly
reduced by megalin competitors. To investigate whether Tg release
resulted from transcytosis, we studied FRTL-5 cells cultured as
polarized layers with tight junctions on permeable filters in the upper
chamber of dual chambered devices. Following the addition of Tg to the
upper chamber and incubation at 37 °C, intact 330-kDa Tg was found
in fluids collected from the lower chamber. The amount recovered was
markedly reduced by megalin competitors, indicating that megalin
mediates Tg transcytosis. We also studied Tg transcytosis in
vivo, using a rat model of goiter induced by aminotriazole, in
which increased release of thyrotropin induces massive colloid
endocytosis. This was associated with increased megalin expression on
thyrocytes and increased serum Tg levels, with reduced serum T3 levels,
supporting the conclusion that megalin mediates Tg transcytosis. Tg
transcytosis is a novel function of megalin, which usually transports
ligands to lysosomes. Megalin-mediated transcytosis may regulate the
extent of thyroid hormone release.
Role of Megalin (gp330) in Transcytosis of Thyroglobulin by
Thyroid Cells
A NOVEL FUNCTION IN THE CONTROL OF THYROID HORMONE RELEASE*
§¶,,
,, and
Pathology Research Laboratory and the
Program in Membrane Biology, Massachusetts General Hospital,
Harvard Medical School, Charlestown, Massachusetts 02129 and the
§ Department of Endocrinology, University of Pisa,
Pisa, Italy 56124
*
This work was supported by NIDDK, National Institutes of
Health Grants 46301 (to R. T. M.) and DK42956 (D. B.); by Grants from the National Research Council (Consiglio Nazionale Ricerche, Roma,
Italy) (Target Project Biotechnology and Bioinstrumentation Grant
91.01219 and Target Project Prevention and Control of Disease Factors
Grant 93.00437); and by EEC Stimulation Action-Science Plan Contract
SC1-CT91-0707.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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