Dietary iodide controls its own absorption through post-transcriptional regulation of the intestinal Na+/I- symporter

Key points Expression of the Na+/I-symporter (NIS) at the apical surface of the epithelium of the small intestine is key to I-absorption, the first step in I-metabolism. Intracellular I-at high concentrations in enterocytes decreases its own NIS-mediated uptake by a newly discovered mechanism, downregulating NIS expression at the plasma membrane, increasing NIS protein degradation and decreasing NIS mRNA levels by reducing NIS mRNA stability, involving the NIS 3'-untranslated region. In conclusion, we have uncovered that I-regulates intestinal NIS expression, and thus its own intestinal absorption, by a complex array of post-transcriptional mechanisms. Abstract Dietary I-absorption in the gastrointestinal tract is the first step in I-metabolism. Given that I-is an essential constituent of the thyroid hormones, its concentrating mechanism is of significant physiological importance. We recently described the expression of the Na+/I-symporter (NIS) on the apical surface of the intestinal epithelium as a central component of the I-absorption system and reported reduced intestinal NIS expression in response to an I--rich diet in vivo. Here, we evaluated the mechanism involved in the regulation of NIS expression by I-itself in enterocytes. Excess I-reduced NIS-mediated I-uptake in IEC-6 cells in a dose-and time-dependent fashion, which was correlated with a reduction of NIS expression at the plasma membrane. Perchlorate, a competitive inhibitor of NIS, prevented these effects, indicating that an increase in intracellular I-regulates NIS. Iodide induced rapid intracellular recruitment of plasma membrane NIS molecules and NIS protein degradation. Lower NIS mRNA levels were detected in response to I-treatment, although no transcriptional effect was observed. Interestingly, I-decreased NIS mRNA stability, affecting NIS translation. Heterologous green fluorescent protein-based reporter constructs revealed a significant repressive effect of the I-targeting NIS mRNA 3' untranslated region. In conclusion, excess I-downregulates NIS expression in enterocytes by virtue of a complex mechanism. Our data suggest that I-regulates intestinal NIS mRNA expression at the post-transcriptional level as part of an autoregulatory effect of I-on its own metabolism.