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ADAR1 previene la autoinflamación al suprimir la activación espontánea de ZBP1
Richard de Reuver1,2, Simon Verdonck1,2, Evelien Dierick1,2
1VIB-UGent Center for Inflammation Research, Ghent, Belgium.
Nature
|July 21, 2022
Resumen
La enzima de edición de ARN ADAR1 normalmente impide que el propio ARN desencadene respuestas inmunes. La pérdida de ADAR1 activa ZBP1, lo que lleva a la muerte celular y la inflamación, lo que contribuye al síndrome de Aicardi-Goutières.
Área de la Ciencia:
- Inmunología
- Biología molecular
- La genética
Sus antecedentes:
- ADAR1 (adenosina desaminasa que actúa sobre el ARN 1) limita el ARN de doble cadena inmunostimulador (dsRNA).
- La actividad reducida de ADAR1 causa el síndrome de Aicardi-Goutières (AGS) en humanos y la autoinflamación en ratones.
- La edición A-to-I de ADAR1 previene la sobreactivación de los sensores de dsRNA MDA5 y PKR.
Objetivo del estudio:
- Investigar el papel de ADAR1 en la inhibición de la activación de ZBP1.
- Aclarar los mecanismos por los que la activación de ZBP1 contribuye a las patologías relacionadas con la deficiencia de ADAR1.
- Determinar el papel del dominio Zα de ADAR1 en la prevención de la muerte celular y la inflamación mediadas por ZBP1.
Principales métodos:
- Análisis de células con deficiencia de ADAR1 y modelos de ratón.
- Evaluación de la activación de ZBP1, la apoptosis y la necroptosis.
- Investigación de la función del dominio Zα de ADAR1 en la edición de elementos Alu.
Principales resultados:
- ADAR1 inhibe la activación espontánea de ZBP1.
- La activación de ZBP1 provoca la apoptosis dependiente de la caspasa-8 y la necroptosis mediada por MLKL en las células deficientes en ADAR1.
- ZBP1 contribuye a la letalidad embrionaria en ratones con ADAR knockout y la mortalidad en ratones con deficiencia de ADAR/MAVS.
- El dominio Zα de ADAR1 previene la muerte celular intestinal mediada por ZBP1 y la inflamación de la piel mediante la edición de elementos Alu.
Conclusiones:
- ADAR1 previene la muerte celular y la inflamación mediadas por ZBP1.
- La activación de ZBP1 por Alu dsRNA contribuye a la patogénesis de AGS en escenarios de pérdida de función de ADAR1.
- Dirigirse a ZBP1 o mejorar la actividad de ADAR1 puede ofrecer estrategias terapéuticas para AGS.
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