Analysis of transcription mechanisms that limit type i interferon responses
- Autores: Hector Huerga Encabo
- Directores de la Tesis: Cristina López Rodríguez (dir. tes.), José Francisco Aramburu Beltrán (codir. tes.)
- Lectura: En la Universitat Pompeu Fabra ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: Anna Bigas Salvans (presid.), Annabel Fernández Valledor (secret.), Ana Angulo Aguado (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad Pompeu Fabra
- Materias:
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- Resumen
Activation of IFN-I production has pleiotropic and diverse effects depending on the cell type that sense IFN-I. In this thesis, we characterize NFAT5 as a negative regulator of the expression of IFN-I genes. This work defines for the first time a precise molecular mechanism that inhibits the expression of IFNB1. We show that NFAT5 binds the IFNB1 promoter. We identified a binding site for NFAT5 at the IFNB1 promoter that overlaps with a binding site for IRF3, the master regulator of IFNβ. This overlapping causes a competition between IRF3 and NFAT5 that limits IFNβ production. We characterized how NFAT5 deficiency in vivo cause enhanced activation of the IFN-I pathway and improved control of viral load, but also could lead exacerbated HSC exit from quiescence, making them vulnerable to exhaustion. These results highlight the complex balance between beneficial and detrimental effects of increasing IFN-I response. Overall this thesis confirms NFAT5 as a pleiotropic regulator of innate immune responses.
