Involvement of oxidative reactions and extracellular protein chaperones in the rescue of misassembled thyroglobulin in the follicular lumen.
Reactive oxygen species (ROS) are involved in many pathological processes through modifications of structure and activity of proteins. ROS also participate in physiological pathways such as thyroid hormone biosynthesis, which proceeds through oxidation of the prothyroid hormone (thyroglobulin, Tg) and iodide. Regarding the colloidal insoluble multimerized Tg (m-Tg), which bears dityrosine bridges and is present in the follicular lumen, a mild oxidative system generated different soluble forms of Tg, more or less compacted by hydrophobic associations, and linked with Grp78 and Grp94. In vitro, the combined action of ROS and PDI, in the presence of free glutathione (reduced/oxidized), increased the solubility of this misassembled Tg and partially restored the ability of Tg to synthesize hormones. Our results show that protein chaperones escape from the ER and are involved with ROS in thyroid hormone synthesis. Therefore, we propose a model of roles of m-Tg in the follicular lumen.
Unité 38 INSERM, Faculté de Médecine, Marseille, France.
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Delom
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Lejeune
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Vinet
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Carayon
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Mallet
D002352:Carrier Proteins / Q000302:isolation & purification; D005591:Chemical Fractionation; D000091342:Endoplasmic Reticulum Chaperone BiP; D005110:Extracellular Space / Q000502:physiology*; D006042:Goiter / Q000378:metabolism / Q000473:pathology; D018840:HSP70 Heat-Shock Proteins / Q000302:isolation & purification; D006360:Heat-Shock Proteins; D006801:Humans; D006868:Hydrolysis; D008565:Membrane Proteins / Q000302:isolation & purification; D008954:Models, Biological; D018832:Molecular Chaperones / Q000302:isolation & purification / Q000502:physiology*; D010084:Oxidation-Reduction; D011108:Polymers / Q000737:chemistry; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D017510:Protein Folding; D017382:Reactive Oxygen Species / Q000502:physiology*; D012995:Solubility; D013954:Thyroglobulin / Q000737:chemistry / Q000378:metabolism*; D013961:Thyroid Gland / Q000378:metabolism* / Q000473:pathology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D011108:Polymers; D017382:Reactive Oxygen Species; C018551:glucose-regulated proteins; D014443:Tyrosine; D013954:Thyroglobulin; C007543:dityrosine; D019704:Protein Disulfide-Isomerases