S-Nitrosylation of NF-κB p65 Inhibits TSH-Induced Na+/I− Symporter Expression

• Published in: Endocrinology (Philadelphia) 2015-12, Vol.156 (12), p.4741-4754
• Main Authors: Nicola, Juan Pablo, Peyret, Victoria, Nazar, Magalí, Romero, Jorge Miguel, Lucero, Ariel Maximiliano, Montesinos, María del Mar, Bocco, José Luis, Pellizas, Claudia Gabriela, Masini-Repiso, Ana María
• Format: Article
• Language: English
• Subjects: Animals; Autocrine Communication; Autocrine signalling; Biosynthesis; Cell Line; Gene expression; Gene Expression Regulation - drug effects; Gene silencing; Iodides; Iodine - metabolism; Molecular modelling; NF-κB protein; NIS gene; NIS protein; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase Type III - metabolism; Nitroprusside - pharmacology; Promoter Regions, Genetic; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - drug effects; RNA, Messenger - metabolism; S-Nitrosoglutathione - pharmacology; Spermine - analogs & derivatives; Spermine - pharmacology; Symporters - drug effects; Symporters - genetics; Thyroid; Thyroid gland; Thyroid Gland - cytology; Thyroid Gland - drug effects; Thyroid Gland - metabolism; Thyroid-stimulating hormone; Thyrotropin - metabolism; Transcription Factor RelA - drug effects; Transcription Factor RelA - metabolism; Transcriptional Activation - drug effects
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2015-1192

Nitric oxide (NO) is a ubiquitous signaling molecule involved in a wide variety of cellular physiological processes. In thyroid cells, NO-synthase III-endogenously produced NO reduces TSH-stimulated thyroid-specific gene expression, suggesting a potential autocrine role of NO in modulating thyroid function. Further studies indicate that NO induces thyroid dedifferentiation, because NO donors repress TSH-stimulated iodide (I−) uptake. Here, we investigated the molecular mechanism underlying the NO-inhibited Na+/I− symporter (NIS)-mediated I− uptake in thyroid cells. We showed that NO donors reduce I− uptake in a concentration-dependent manner, which correlates with decreased NIS protein expression. NO-reduced I− uptake results from transcriptional repression of NIS gene rather than posttranslational modifications reducing functional NIS expression at the plasma membrane. We observed that NO donors repress TSH-induced NIS gene expression by reducing the transcriptional activity of the nuclear factor-κB subunit p65. NO-promoted p65 S-nitrosylation reduces p65-mediated transactivation of the NIS promoter in response to TSH stimulation. Overall, our data are consistent with the notion that NO plays a role as an inhibitory signal to counterbalance TSH-stimulated nuclear factor-κB activation, thus modulating thyroid hormone biosynthesis.