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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
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La desacetilasa dependiente de NAD SIRT2 es necesaria para la necrosis programada
Nisha Narayan1, In Hye Lee, Ronen Borenstein
1Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland 20892, USA.
Nature
|December 4, 2012
Resumen
SIRT2 regula la necrosis programada mediante la desacetilación de RIP1, evitando la formación de complejos RIP1-RIP3. La inhibición de SIRT2 protege contra lesiones como la isquemia-reperfusión, lo que sugiere un potencial terapéutico para la necrosis.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Biología celular Biología celular.
- La bioquímica es la bioquímica.
Sus antecedentes:
- La necrosis celular, una vez considerada no regulada, ahora se entiende que sigue vías moleculares específicas.
- El factor de necrosis tumoral alfa (TNF-α) desencadena la necrosis a través de la formación de un complejo de proteína 1 que interactúa con el receptor (RIP1) y proteína 3 que interactúa con el receptor (RIP3).
- La regulación de esta formación compleja RIP1-RIP3 sigue siendo en gran medida desconocida.
Objetivo del estudio:
- Investigar el papel de SIRT2 en la regulación de la necrosis programada.
- Para determinar si SIRT2 modula la formación del complejo RIP1-RIP3.
- Evaluar el potencial terapéutico de la inhibición de SIRT2 en condiciones que involucran necrosis.
Principales métodos:
- Se evaluó la unión constitutiva de SIRT2 a RIP3.
- Se realizó la eliminación o eliminación de SIRT2 en ratones para evaluar su efecto en la formación del complejo RIP1-RIP3.
- La necrosis inducida por TNF-α se midió en presencia de inhibición genética o farmacológica de SIRT2.
- La desacetilación de RIP1 y su efecto en la formación y necrosis de complejos RIP1-RIP3 se analizaron utilizando mutantes de ganancia y pérdida de función.
- Se utilizaron modelos de lesiones por isquemia-reperfusión para evaluar el papel in vivo de SIRT2.
Principales resultados:
- La SIRT2 se une constitutivamente al RIP3, y su ausencia impide la formación del complejo RIP1-RIP3.
- La inhibición de la SIRT2 bloquea la necrosis celular inducida por el TNF-α.
- RIP1 es un objetivo clave de la desacetilación dependiente de SIRT2, con la acetilación de la lisina 530 de RIP1 que modula la formación de complejos y la necrosis.
- La inhibición de SIRT2 protege contra la lesión por isquemia-reperfusión in vivo.
Conclusiones:
- SIRT2 es un regulador crítico de la necrosis programada.
- Dirigirse a SIRT2 con inhibidores puede ofrecer una nueva estrategia terapéutica para lesiones necróticas, incluido el accidente cerebrovascular isquémico y el infarto de miocardio.
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