Hoffsmith, K. | Search bioRxiv

bioRxiv2025

Engineering substrate selectivity in the human sodium/iodide symporter (NIS)

Iodide (I-) uptake mediated by the Na/I- symporter (NIS) is the first step in the biosynthesis of the thyroid hormones, of which I- is an essential constituent. NIS couples the inward transport of I- against its electrochemical gradient to the inward translocation of Na+ down its electrochemical gradient. NIS also transports oxyanions (XO4-s), such as perrhenate (ReO4-) and the environmental pollutant perchlorate (ClO4-). Furthermore, NIS is the basis for radioiodide ({superscript 1}3{superscript 1}I-) therapy for thyroid cancer (administered after thyroidectomy), the most effective targeted internal radiation cancer therapy available. 131I- selectively targets remnant malignant cells and metastases expressing NIS, causing only minor side effects. There is great interest in expressing NIS exogenously, by gene transfer, in extrathyroidal cancers to render them susceptible to destruction by 131I-. This approach, however, would also harm patients thyroids. Therefore, a strategy is needed for killing non-thyroidal cancer cells exogenously expressing NIS while protecting the thyroid. Addressing this need, we present here an engineered double mutant, L253P/V254F (PF)-NIS, which selectively transports XO4-s but not I-. We used cryo-EM to determine the structure of PF-NIS with ReO4- and Na+ ions bound to it at a 2.58 [A] resolution, and showed that high concentrations of non-radioactive I- protect WT-NIS-expressing cells from radioactive 186ReO4-, whereas PF-NIS-expressing cells are killed. Thus, PF-NIS could potentially be used, together with 186/188ReO4- and non-radioactive I-, to treat non-thyroidal cancers while safeguarding the thyroid. This study establishes a framework for developing therapies using NIS molecules engineered to have selective substrate specificities to extend the clinical use of NIS beyond thyroid cancer.

biophysics↗

bioRxiv2025

Overnutrition directly impairs thyroid hormone biosynthesis and utilization, causing hypothyroidism, despite remarkable thyroidal adaptations

Thyroid hormones (THs: T3 and T4) are key regulators of metabolic rate and nutrient metabolism. They are controlled centrally and peripherally in a coordinated manner to elegantly match T3-mediated energy expenditure (EE) to energy availability. Hypothyroidism reduces EE and has long been blamed for obesity; however, emerging evidence suggests that, instead, obesity may drive thyroid dysfunction. Thus, we used a mouse model of diet-induced obesity to determine its direct effects on thyroid histopathology and function, deiodinase activity, and T3 action. Strikingly, overnutrition induced hypothyroidism within 3 weeks. Levels of thyroidal THs and their precursor protein thyroglobulin decreased, and ER stress was induced, indicating that thyroid function was directly impaired. We also observed pronounced histological and vascular expansion in the thyroid. Overnutrition additionally suppressed T4 activation, rendering the mice resistant to T4 and reducing EE. Our findings collectively show that overnutrition deals a double strike to TH biosynthesis and action, despite large efforts to adapt--but, fortunately, thyroid dysfunction in mice can be reversed by weight loss. In humans, BMI correlated with thyroidal vascularization, importantly demonstrating preliminary translatability. These studies lay the groundwork for novel obesity therapies that tackle hypothyroidism--which are much-needed, as no current obesity treatment works for everyone.

physiology↗