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Mixed-Disulfide Folding Intermediates between Thyroglobulin and Endoplasmic Reticulum Resident Oxidoreductases ERp57 and Protein Disulfide Isomerase

Laboratorio di Patologia Generale, Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Facoltà di Scienze MFN, Università degli Studi di Lecce, Centro Ecotekne, 73100 Lecce, Italy,¹ Istituto di Endocrinologia ed Oncologia Sperimentale del C.N.R. "G. Salvatore" e Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli "Federico II," Napoli, Italy,³ Faculty of Life Sciences, University of Manchester, Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom,⁴ Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, 1500 W. Medical Ctr. Dr., Ann Arbor, Michigan 48109²

Received 19 February 2005/ Returned for modification 2 May 2005/ Accepted 29 August 2005

We present the first identification of transient folding intermediates of endogenous thyroglobulin (Tg; a large homodimeric secretory glycoprotein of thyrocytes), which include mixed disulfides with endogenous oxidoreductases servicing Tg folding needs. Formation of disulfide-linked Tg adducts with endoplasmic reticulum (ER) oxidoreductases begins cotranslationally. Inhibition of ER glucosidase activity blocked formation of a subgroup of Tg adducts containing ERp57 while causing increased Tg adduct formation with protein disulfide isomerase (PDI), delayed adduct resolution, perturbed oxidative folding of Tg monomers, impaired Tg dimerization, increased Tg association with BiP/GRP78 and GRP94, activation of the unfolded protein response, increased ER-associated degradation of a subpopulation of Tg, partial Tg escape from ER quality control with increased secretion of free monomers, and decreased overall Tg secretion. These data point towards mixed disulfides with the ERp57 oxidoreductase in conjunction with calreticulin/calnexin chaperones acting as normal early Tg folding intermediates that can be "substituted" by PDI adducts only at the expense of lower folding efficiency with resultant ER stress.

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