title: Oxidoreductase interactions include a role for ERp72 engagement with mutant thyroglobulin from the rdw/rdw rat dwarf.
abstract: Newly synthesized thyroglobulin (Tg), the secretory glycoprotein that serves as precursor in thyroid hormone synthesis, normally forms transient covalent protein complexes with oxidoreductases of the endoplasmic reticulum (ER). The Tg-G2320R mutation is responsible for congenital hypothyroidism in rdw/rdw rats, in which a lack of secondary thyroid enlargement (goiter) implicates death of thyrocytes as part of disease pathogenesis. We found that mutant Tg-G2320R was retained within the ER with no detectable synthesis of thyroxine, had persistent exposure of free cysteine thiols, and was associated with activated ER stress response but incomplete ER-associated degradation (ERAD). Tg-G2320R associated with multiple ER resident proteins, most notably ERp72, including covalent Tg-ERp72 interactions. In PC Cl3 thyrocytes, inducible overexpression of ERp72 increased the ability of cells to maintain Tg cysteines in a reduced state. Noncovalent interactions of several ER chaperones with newly synthesized Tg-G2320R diminished over time in parallel with ERAD of the mutant protein, yet a small ERAD-resistant Tg fraction remained engaged in covalent association with ERp72 even 2 days post-synthesis. Such covalent protein aggregates may set the stage for apoptotic thyrocyte cell death, preventing thyroid goiter formation in rdw/rdw rats.
authors.affiliation: Program in Cell and Molecular Biology and Division of Endocrinology, University of Cincinnati, Ohio 45267, USA.
authors.forename: Shekar
authors.initials: S
authors.lastname: Menon
authors.forename: Jaemin
authors.initials: J
authors.lastname: Lee
authors.forename: William A
authors.initials: WA
authors.lastname: Abplanalp
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Yoo
authors.forename: Takashi
authors.initials: T
authors.lastname: Agui
authors.forename: Sen-Ichi
authors.initials: S
authors.lastname: Furudate
authors.forename: Paul S
authors.initials: PS
authors.lastname: Kim
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
mesh_terms: D000818:Animals; D017209:Apoptosis; D004392:Dwarfism / Q000209:etiology* / Q000378:metabolism; D004721:Endoplasmic Reticulum; D006042:Goiter; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D010088:Oxidoreductases / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D011922:Rats, Mutant Strains; D013954:Thyroglobulin / Q000235:genetics* / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology
chemical_list: D008562:Membrane Glycoproteins; C062477:endoplasmic reticulum glycoprotein p72; D013954:Thyroglobulin; D010088:Oxidoreductases