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OTULIN limita la muerte celular y la inflamación al desbiquitar el LUBAC
Klaus Heger1, Katherine E Wickliffe1, Ada Ndoja1
1Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
Nature
|June 29, 2018
Resumen
La proteína OTULIN previene la autoubiquitinación de LUBAC, un complejo crítico para prevenir la inflamación y la letalidad embrionaria. La pérdida de la función de OTULIN conduce a la muerte celular y a la producción de interferón tipo I.
Área de la Ciencia:
- Biología celular
- Inmunología
- Biología molecular
Sus antecedentes:
- OTULIN (OTU deubiquitinasa con especificidad de enlace lineal) elimina la poliubiquitina lineal de los sustratos LUBAC (complejo de ensamblaje de cadena de ubiquitina lineal).
- OTULIN es crucial para prevenir las enfermedades autoinflamatorias y la letalidad embrionaria.
Objetivo del estudio:
- Investigar el papel preciso de OTULIN en la regulación de la actividad de LUBAC y sus consecuencias posteriores.
- Aclarar los mecanismos por los que la deficiencia de OTULIN conduce a la letalidad embrionaria y la autoinflamación.
Principales métodos:
- Generación de ratones knock-in que expresan OTULIN catalíticamente inactivo.
- Análisis de las vías de muerte celular (TNFR1, RIPK1, caspasa 8, RIPK3) en modelos con deficiencia de OTULIN.
- Evaluación de la producción de interferón de tipo I en ratones mutantes.
Principales resultados:
- OTULIN catalizador inactivo fenocopia la deficiencia de LUBAC, causando la letalidad embrionaria en la gestación debido a la muerte celular mediada por TNFR1/ RIPK1.
- La inactivación de OTULIN en ratones adultos desencadena la muerte celular proinflamatoria, que es rescatada por la pérdida combinada de caspasa 8 y RIPK3.
- Los ratones mutantes de OTULIN que carecen de caspasa 8 y RIPK3 muestran letalidad perinatal con una mayor producción de interferón tipo I dependiente de RIPK1.
Conclusiones:
- OTULIN y LUBAC funcionan en una vía lineal, con OTULIN promoviendo la actividad de LUBAC impidiendo su autoubiquitinación.
- OTULIN juega un papel crítico en la regulación de las vías de muerte celular y la inducción de interferón tipo I.
- Estos hallazgos revelan un nuevo vínculo entre la ubiquitinación lineal, la muerte celular y las respuestas inmunes innatas.
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