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La conjugación similar a la ubiquitina por el cGAS bacteriano mejora la defensa antifágico
Justin M Jenson1,2, Tuo Li1,2,3, Fenghe Du1,2,3
1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature
|February 27, 2023
Resumen
Las bacterias usan un mecanismo similar a la ubiquitina para controlar la actividad de la enzima cGAS contra las infecciones de los fagos. Esto implica la conjugación de proteínas para aumentar la producción de GMP-AMP cíclico (cGAMP), que los fagos luego contrarrestan secuestrando cGAMP.
Área de la Ciencia:
- Microbiología
- Biología molecular
- Inmunología
Sus antecedentes:
- La GMP-AMP sintasa cíclica (cGAS) es crucial para la defensa inmune en los vertebrados al producir cGAMP en la detección de ADN.
- Las bacterias poseen sistemas de señalización antifágicos (CBASS) basados en dinucleótidos cíclicos (CDN) que involucran enzimas y efectores similares al cGAS para combatir las infecciones de los fagos.
- Algunos sistemas CBASS incluyen proteínas Cap2 y Cap3, homólogas a las enzimas conjugadoras de ubiquitina, pero su mecanismo antifágico sigue sin estar claro.
Objetivo del estudio:
- Para dilucidar el mecanismo antifágico de las proteínas Cap2 y Cap3 dentro de la CBASS bacteriana.
- Investigar cómo se regulan las enzimas bacterianas similares al cGAS durante la infección de los fagos.
- Comprender las bases moleculares de la defensa bacteriana contra los fagos y las estrategias virales.
Principales métodos:
- Se investigó la interacción entre Cap2 y cGAS utilizando ensayos bioquímicos.
- Se analizó el efecto de la conjugación mediada por Cap2 en la producción de cGAMP.
- Se empleó el cribado genético para identificar proteínas fagas que antagonizan la señalización bacteriana de cGAS.
- Se determinó la estructura cristalina de una proteína de fago unida al cGAMP.
Principales resultados:
- Se demostró que Cap2 conjuga cGAS a las proteínas objetivo a través de un enlace tioéster, imitando la conjugación de la ubiquitina.
- Se demostró que esta modificación covalente de cGAS mejora la producción cíclica de GMP-AMP (cGAMP).
- Identificó una proteína fagal, Vs.4, que se une fuertemente a la cGAMP, secuestrándola e inhibiendo la defensa bacteriana.
- Reveló la estructura hexámica de Vs.4 unida a cGAMP, explicando su mecanismo inhibidor.
Conclusiones:
- La actividad bacteriana de cGAS está regulada por un mecanismo de conjugación similar a la ubiquitina que involucra a Cap2.
- La defensa bacteriana contra los fagos implica la modulación de los niveles de dinucleótidos cíclicos.
- Los fagos han desarrollado mecanismos, como Vs.4, para contrarrestar las defensas bacterianas al interferir con la señalización cGAMP, destacando una carrera armamentista evolutiva.
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