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Sortilin Is a Putative Postendocytic Receptor of Thyroglobulin

Departments of Endocrinology and Metabolism (R.B., S.L., A.P., C.M., M.M), Neuroscience (F.G), and Human Morphology and Applied Biology (N.B., C.I.), University of Pisa, 56124 Pisa, Italy; Department of Environmental Science (A.R.T., A.M.F), University of the Tuscia, 01100 Viterbo, Italy; Department of Medical Sciences and Laboratory of Experimental Endocrinology (L.P., D.C.), University of Milan and Istituto di Ricovero e Cura a Carattere Scientifico Istituto Auxologico Italiano, 20095 Cusano Milanino, Italy; and MIND Center, Institute of Medical Biochemistry (P.M., C.M.P.), Aarhus University, D-8000 Aarhus, Denmark

Address all correspondence and requests for reprints to: Michele Marinò M.D., Department of Endocrinology, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy. E-mail: m.marino{at}endoc.med.unipi.it.

The Vps10p family member sortilin is involved in various cell processes, including protein trafficking. Here we found that sortilin is expressed in thyroid epithelial cells (thyrocytes) in a TSH-dependent manner, that the hormone precursor thyroglobulin (Tg) is a high-affinity sortilin ligand, and that binding to sortilin occurs after Tg endocytosis, resulting in Tg recycling. Sortilin was found to be expressed intracellularly in thyrocytes, as observed in mouse, human, and rat thyroid as well as in FRTL-5 cells. Sortilin expression was demonstrated to be TSH dependent, both in FRTL-5 cells and in mice treated with methimazole and perchlorate. Plasmon resonance binding assays showed that Tg binds to sortilin in a concentration-dependent manner and with high affinity, with K_d values that paralleled the hormone content of Tg. In addition, we found that Tg and sortilin interact in vivo and in cultured cells, as observed by immunoprecipitation, in mouse thyroid extracts and in COS-7 cells transiently cotransfected with sortilin and Tg. After incubation of FRTL-5 cells with exogenous, labeled Tg, sortilin and Tg interacted intracellularly, presumably within the endocytic pathway, as observed by immunofluorescence and immunoelectron microscopy, the latter technique showing some degree of Tg recycling. This was confirmed in FRTL-5 cells in which Tg recycling was reduced by silencing of the sortilin gene and in CHO cells transfected with sortilin in which recycling was increased. Our findings provide a novel pathway of Tg trafficking and a novel function of sortilin in the thyroid gland, the functional impact of which remains to be established.