Involvement of oxidative reactions and extracellular protein chaperones inthe rescue of misassembled thyroglobulin in the follicular lumen

Reactive oxygen species (ROS) are involved in many pathological processes t hrough modifications of structure and activity of proteins. ROS also partic ipate in physiological pathways such as thyroid hormone biosynthesis, which proceeds through oxidation of the prothyroid hormone (thyroglobulin, Tg) a nd iodide. Regarding the colloidal insoluble multimerized Tg (m-Tg), which bears dityrosine bridges and is present in the follicular lumen, a mild oxi dative system generated different soluble forms of Tg, more or less compact ed by hydrophobic associations, and linked with Grp78 and Grp94. In vitro, the combined action of ROS and PDI, in the presence of free glutathione (re duced/oxidized), increased the solubility of this misassembled Tg and parti ally restored the ability of Tg to synthesize hormones, Our results show th at protein chaperones escape from the ER and are involved with ROS in thyro id hormone synthesis. Therefore, we propose a model of roles of m-Tg in the follicular lumen. (C) 1999 Academic Press.