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The capture of iodide is a vital process in vertebrates. It occurs mainly in the thyroid gland and constitutes the first and limiting step in the biosynthesis of iodinated hormones T3 and T4. This transport is known to be mediated by the sodium iodide symporter (NIS), an integral membrane glycoprotein that transports iodide against its electrochemical gradient. [1] Iodide capture plays a central role in many thyroid pathophysiological conditions. Impaired iodide uptake is observed in Grave's and Hashimoto's diseases, thyroiditis, adenoma and thyroid cancers, cold nodules, goitre and hypothyroidism. Several studies conclude that thyroid gland failure occurs in 5-7 % of populations across different countries.[2] There is also an important concern when people are accidentally exposed to radioiodine species since its accumulation in the thyroid gland increases the risk of cancer, especially in the youngest population. A dramatic example of this is the Chernobyl accident in 1986 after which the World Health Organization (WHO) predicted that 9 000 individuals would die from cancer as a direct result of this disaster.[3] Iodide uptake is also at the basis of an emerging strategy to monitor and kill cancer cells using radioiodide after targeted NIS gene transfer.[4] Unfortunately, this strategy is not yet amenable to clinical applications because transport capacities in these transformed cells is too low for efficient tumor destruction. Understanding how iodide capture is mediated and regulated at a cellular level remains a fundamental area of research. The cloning of NIS in 1996 [5] led to great advances in the molecular characterization of the symporter, and many studies have been conducted since then to investigate NIS expression and NIS transcriptional regulation mechanisms. [1a, 4b, c, 6] However, the molecular aspects of how iodide is translocated inside the thyroid cells, how this capture is up-regulated at a cellular level, and which proteins are involved in post-translational regulation of NIS activity are still unknown. It is necessary to understand the whole mechanistic picture of iodide capture in NIS-expressing cells in order to develop new therapeutic tools and improve the clinical management of patients.Recently, a new compound, iodide transport blocker 5 (ITB5) was discovered by high-throughput screening as a very potent iodide uptake blocker in human embryonic kidney cells stably expressing human NIS (hNIS-HEK293), as well as in the rat thyroid-derived cells FRTL5. [7] ITB5 was shown to be a powerful inhibitor with a half maximal inhibitory concentration (IC 50 ) value of 40 nm. Further analysis of the effect of ITB5 on iodide-induced current in NIS-expressing Xenopus oocytes showed that the inhibition was rapid (< 5 s) and reversible.[8]These results indicated that ITB5 acts by disrupting NIS either directly or at a post-translational level. Consequently, this compound opens new, promising perspectives to dissect the cellular regulation mechanisms of iodide capture using chemical proteomics and affi...

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