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Las toxinas virales y metazoares son nucleasas específicas de cGAMP que restringen la señalización de cGAS-STING

James B Eaglesham^1,2,3, Youdong Pan⁴, Thomas S Kupper^4,5

¹Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.

|February 8, 2019

Resumen

Las nucleasas inmunes (poxinas) del virus de la viruela se degradan 2

Área de la Ciencia:

Inmunología
Virología
Biología estructural

Sus antecedentes:

El ADN citosólico activa la inmunidad innata a través de la GMP-AMP sintasa cíclica (cGAS) y la GMP-AMP 2',3'-cíclica (cGAMP).
La vía STING es crucial para la señalización inmune, pero carece de inhibidores endógenos conocidos de 2',3'-cGAMP.
Los virus han desarrollado mecanismos para evadir las respuestas inmunes innatas del huésped.

Objetivo del estudio:

Identificar el huésped o los factores virales que degradan el 2',3'-cGAMP.
Caracterizar la función y el mecanismo de las nuevas enzimas degradantes de 2',3'-cGAMP.
Investigar el papel de estas enzimas en la patogénesis viral y la evasión inmune innata.

Principales métodos:

Evaluación bioquímica de 24 virus de mamíferos.
Ensayos de actividad enzimática para la degradación de 2',3'-cGAMP.
Determinación de la estructura cristalina de la toxina del virus de la vacuna.
Estudios de deleción de genes en el virus de la vacuna.
Análisis bioinformático de los homólogos de las toxinas en insectos y baculovirus.

Principales resultados:

Se identificaron las nucleasas inmunes del virus de la viruela (poxinas) como enzimas degradantes de 2',3'-cGAMP.
Las poxinas se dividen en 2',3'-cGAMP, lo que restringe la señalización dependiente de STING.
La eliminación del gen de la poxina del virus de la vacuna (B2R) redujo la replicación viral in vivo.
Las estructuras cristalinas revelaron un mecanismo independiente del metal para la hidrólisis selectiva de 2',3'-cGAMP.
Se encontraron homólogos de la poxina conservados en los poxvirus de insectos y sus huéspedes, lo que sugiere un papel antiguo.

Conclusiones:

Las poxinas representan una nueva familia de nucleasas específicas de 2',3'-cGAMP.
Los virus utilizan las toxinas para degradar 2',3'-cGAMP y evadir la inmunidad innata mediada por cGAS-STING.
Las toxinas juegan un papel importante en la patogénesis del virus de la viruela y tienen una historia evolutiva antigua vinculada a la regulación de cGAS-STING.

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