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La ubiquitinación lineal previene la inflamación y regula la señalización inmune
Björn Gerlach1, Stefanie M Cordier, Anna C Schmukle
1Tumour Immunology Unit, Department of Medicine, Imperial College London, W12 0NN London, UK.
Nature
|April 2, 2011
Resumen
SHARPIN se identifica como una proteína clave en la señalización inmune. Previene la muerte celular y la inflamación inducida por el TNF mediante la regulación de la ubiquitinación lineal in vivo.
Área de la Ciencia:
- Inmunología Inmunología.
- Biología Molecular Biología Molecular
- La señalización celular.
Sus antecedentes:
- Los miembros de la superfamilia de receptores del factor de necrosis tumoral (TNF) son cruciales para la inmunidad y la inflamación.
- Las cadenas lineales de ubiquitina, ensambladas por HOIL-1 y HOIP, estuvieron implicadas en la señalización del TNF, pero su relevancia in vivo no estaba clara.
Objetivo del estudio:
- Para identificar los componentes del complejo de ensamblaje de la cadena de ubiquitina lineal involucrado en la señalización del TNF.
- Para investigar el papel in vivo de SHARPIN en la regulación inmune y la inflamación.
Principales métodos:
- Espectrometría de masas para analizar los complejos de señalización del TNF.
- Análisis de mutación genética del gen Sharpin (Sharpin (((cpdm/cpdm)).
- Evaluación de la inducción génica y muerte celular en respuesta al TNF, ligando CD40 e IL-1β.
Principales resultados:
- SHARPIN fue identificado como un tercer componente del complejo de ensamblaje de la cadena de ubiquitina lineal, reclutado para la señalización de los receptores CD40 y TNF.
- Se encontró que RIP1 y NEMO están ubiquitinados linealmente en los complejos de señalización del TNF.
- La mutación de Sharpin (cpdm / cpdm) condujo a dermatitis crónica, deterioro de la organogénesis linfoide, inducción genética atenuada y sensibilidad a la muerte inducida por el TNF.
- La deficiencia del gen Tnf evitó lesiones cutáneas en ratones con CPDM.
Conclusiones:
- SHARPIN permite la ubiquitinación lineal en los complejos de señalización del receptor TNF, inhibiendo la muerte celular inducida por el TNF y previniendo la inflamación.
- La ubiquitinación lineal juega un papel vital in vivo en la prevención de la inflamación y la regulación de la señalización inmune.
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