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La edición de la secuencia proteica de SKN-1A/Nrf1 por péptido:N-glucanasa controla la expresión génica del
Nicolas J Lehrbach1, Peter C Breen2, Gary Ruvkun1
1Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Cell
|April 20, 2019
Resumen
La enzima PNG-1/NGLY1 edita la secuencia de la proteína SKN-1A, convirtiendo la asparagina N-glicosilada en ácido aspártico. Esta edición de la secuencia de proteínas, no la desglucosilación, es crucial para la función de SKN-1A y la proteostasis.
Área de la Ciencia:
- Biología molecular
- Biología celular
- Proteóstasis
Sus antecedentes:
- El proteosoma degrada las proteínas y está regulado por el estrés proteotóxico.
- SKN-1A/Nrf1, un factor de transcripción asociado a ER, detecta la disfunción del proteasoma y regula los genes del proteasoma.
- SKN-1A/Nrf1 se somete a una glicosilación ligada al N.
Objetivo del estudio:
- Investigar el papel de PNG-1/NGLY1 en la función SKN-1A/Nrf1.
- Aclarar el mecanismo por el cual la glicosilación ligada al N regula la actividad de SKN-1A/Nrf1.
- Comprender cómo esta vía contribuye a la proteostasis y la resistencia celular a la proteotoxicidad.
Principales métodos:
- Se investigó la actividad enzimática de PNG-1/NGLY1 en SKN-1A/Nrf1.
- Utilizó la modificación genética para introducir mutaciones de aspartato en los sitios de N-glucosilación.
- Se evaluó el impacto de estas modificaciones en la función de SKN-1A/Nrf1 y la actividad del proteasoma.
- Se examinó el efecto de la hiperactivación de SKN-1A/Nrf1 en la resistencia a la toxicidad del péptido beta amiloide.
Principales resultados:
- PNG-1/NGLY1 convierte los residuos de asparagina N-glucosilados en SKN-1A/Nrf1 en ácido aspártico.
- La introducción genética de aspartatos en estos sitios evita la necesidad de PNG-1/NGLY1, lo que indica que la edición de secuencias es clave.
- Esta vía de edición de secuencias de proteínas dependiente de la desglucosilación es esencial para mantener la expresión y la actividad del proteasoma.
- La hiperactivación de SKN-1A/Nrf1 confiere resistencia a la proteotoxicidad del péptido beta amiloide humano.
Conclusiones:
- La glucosilación ligada al N regula la función SKN-1A/Nrf1 a través de la edición de la secuencia de proteínas dependiente de la desglucosilación.
- Este mecanismo es crítico para mantener la proteostasis y la defensa celular contra la proteotoxicidad.
- La vía explica las funciones distintas de las isoformas de SKN-1, análogas a las de los mamíferos Nrf1 y Nrf2.
Palabras clave:
Glicosilación ligada al NNFE2L1 (en inglés)NFE2L2 y NFE2L2NGLY1 y NGLY2Deficiencia de NGLY1Número de personasNúmero de personasPNG-1 (en inglés)La PNaseNombre de la empresaSKN-1A (en inglés)el bortezomibDesglucosilaciónglicobiologíaenfermedades neurodegenerativasPéptido:N-glicanasaEl proteasomaControl de la calidad de las proteínasEdición de la secuencia de proteínasLa proteostasisMás Videos Relacionados
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