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SLC19A1 transporta dinucleótidos cíclicos inmunoreactivos
Rutger D Luteijn1, Shivam A Zaver2, Benjamin G Gowen3,4
1Department of Molecular and Cell Biology, and Cancer Research Laboratory, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, USA.
Nature
|September 13, 2019
Resumen
Los investigadores identificaron el portador de folato reducido SLC19A1 como el transportador principal de los dinucleótidos cíclicos (CDN) en las células. Este descubrimiento tiene un impacto en la comprensión de las respuestas inmunes, la inmunoterapia contra el cáncer y las enfermedades inflamatorias.
Área de la Ciencia:
- Inmunología
- Biología molecular
- Biología celular
Sus antecedentes:
- La acumulación de ADN citosólico señala la infección, el cáncer y el daño al ADN, activando la vía cGAS-STING.
- La activación de cGAS por el ADN sintetiza el monofosfato cíclico de guanosina-adenosina (2'3'-cGAMP), un segundo mensajero.
- 2'3'-cGAMP activa STING, lo que lleva a la activación de IRF3 y NF-κB y a la producción de interferón de tipo I.
Objetivo del estudio:
- Identificar el mecanismo por el cual los dinucleótidos cíclicos (CDN) atraviesan la membrana celular.
- Comprender el transporte de CDN exógenos cruciales para la activación de la vía STING en las células objetivo.
Principales métodos:
- Pantalla de interferencia CRISPR en todo el genoma para identificar transportadores de CDN.
- Agotamiento y sobreexpresión de transportadores candidatos en células humanas.
- Evaluación de la captación de CDN y respuestas funcionales en varios tipos de células.
Principales resultados:
- El portador de folato reducido SLC19A1 fue identificado como el principal transportador de CDN.
- El agotamiento de SLC19A1 inhibió la captación de CDN y las respuestas funcionales.
- La sobreexpresión de SLC19A1 aumentó la absorción y las respuestas de la CDN.
- El folato, la sulfasalazina y el metotrexato inhiben la absorción de CDN en las células humanas.
Conclusiones:
- SLC19A1 es el transportador principal responsable de la captación celular de las CDN.
- Este hallazgo tiene implicaciones significativas para la inmunoterapia del cáncer, la respuesta del huésped a los patógenos y las enfermedades inflamatorias.
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