A NEW ROLE FOR THE CREB3L1 TRANSCRIPTION FACTOR AS REGULATOR OF THE NA+ /I- SYMPORTER (NIS) IN THYROID CELLS

DI GIUSTO, P; MARTIN, M; FUNES CHABÁN, MACARENA; NICOLA, JP; ALVAREZ, C

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Congreso; Congreso SAIB 2021; 2021

SAIB

CREB3L1 is a transcription factor member of the CREB3 family. It is involved in the regulation of genes encoding the synthesis of proteins required in the secretory pathway (transport factors) as well as the expression of tissue-specific genes such as Col1a1 that encode for type I collagen in osteoblast. We have previously shown that, in thyroid cells, CREB3L1 acts as a downstream effector of the thyroid-stimulating hormone (TSH) promoting the expansion of the Golgi volume. Furthermore, we also showed (SAIB 2019) that changes in CREB3L1 expression affect the Na+/I- Symporter (NIS) levels, and NIS-specific iodide uptake. NIS is responsible for the uptake of iodide in many tissues including the thyroid gland where iodide is incorporated into triiodothyronine (T3) and tetraiodothyronine (T4). The rat NIS gene (Slc5a5) has a minimal promoter located within -199 and -110 bp, and a NIS Upstream Enhancer (NUE) region between -2495 and -2264 bp. The NUE accounts for almost all the transcriptional activity of the NIS promoter and is activated in a thyroid specific manner by the TSH/cAMP signaling pathway. Moreover, it has been shown that some transcription factors, like SREBP-1c and SREBP2, regulate the NIS promoter by directly binding to a region outside the NUE enhancer. The aim of this work was to elucidate the importance of CREB3L1 in the regulation of the NIS promoter in thyroid cells. In silico analysis revealed four putative CREB3L1 binding sites for the transcription factor in regions outside the NUE enhancer. Interestingly, two of these putative binding sites are highly conserved across different species. Using different constructs of the 5?-flanking region of NIS, we show that CREB3L1 putative bindings sites are required for the promoter activity. Moreover, NIS promoter activity was hampered by expression of a CREB3L1 dominant negative construct and after downregulation of CREB3L1. These results indicate that CREB3L1 regulates NIS transcriptional activity and suggest that CREB3L1 can directly interact with its putative DNA binding motif. These findings highlight the role of CREB3L1 in maintaining the homeostasis of the thyroid gland, regulating the adaptation of the secretory pathway as well as the synthesis of thyroid-specific proteins.