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Los polidipeptidos codificados por las repeticiones C9orf72 se unen a los nucleolos, impiden la biogénesis del ARN y

Ilmin Kwon¹, Siheng Xiang¹, Masato Kato¹

¹Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.

Science (New York, N.Y.)

|August 2, 2014

Resumen

Las proteínas de unión al ARN con los dominios serina:arginina (SR) se unen a los hidrogeles hnRNPA2. La fosforilación por CLK1/2 invierte la unión, mientras que los péptidos de la enfermedad C9orf72 causan la muerte celular al interrumpir la biogénesis del ARN.

Área de la Ciencia:

Biología Molecular Biología Molecular
Enfermedades neurodegenerativas Las enfermedades neurodegenerativas.
La bioquímica es la bioquímica.

Sus antecedentes:

Los dominios de repetición de serina:arginina (SR) son cruciales en las proteínas reguladoras del ARN involucradas en el empalme del ARN pre-mensajero.
El dominio de baja complejidad de la ribonucleoproteína A2 heterogénea (hnRNPA2) puede formar polímeros fibrosos y gotas de hidrogel.
Las expansiones del gen C9orf72 están vinculadas a enfermedades neurodegenerativas y producen polipéptidos de repetición GRn y PRn.

Objetivo del estudio:

Para investigar la interacción entre los dominios SR y los hidrogeles hnRNPA2.
Determinar el papel de la fosforilación en la regulación de la unión del dominio SR-hnRNPA2 en el hidrogel.
Examinar los efectos celulares de los péptidos derivados de C9orf72, específicamente GRn y PRn, sobre los hidrogeles de hnRNPA2 y los procesos celulares.

Principales métodos:

Ensayos de unión in vitro utilizando dominios SR y hidrogeles hnRNPA2.
Ensayos de fosforilación utilizando las quinasas 1 y 2 similares a CDC2 (CLK1/2).
Expresión de variantes del dominio SR y péptidos C9orf72 en células de mamíferos.
Estudios de localización celular y evaluación de la biogénesis del ARN y la viabilidad celular.

Principales resultados:

Los dominios SR se unen a los hidrogeles hnRNPA2, y esta unión se invierte mediante la fosforilación de CLK1/2.
Las variantes mutadas de SR a GR se unen a los hidrogeles hnRNPA2 independientemente de CLK1/2 y se localizan en los nucleos de las células.
Los péptidos GRn y PRn derivados de C9orf72 se unen a los hidrogeles hnRNPA2 independientemente de la actividad de CLK1/2, entran en las células, se localizan en los nucleolos e inhiben la biogénesis del ARN, lo que lleva a la muerte celular.

Conclusiones:

La fosforilación por CLK1/2 es un mecanismo regulador clave para la interacción del dominio SR con los hidrogeles hnRNPA2.
Los péptidos derivados de C9orf72 imitan las interacciones del dominio SR pero interrumpen las funciones celulares, lo que sugiere un posible mecanismo patógeno en enfermedades neurodegenerativas.
Los hallazgos destacan el papel de las interacciones aberrantes proteína-ácido nucleico en la patogénesis de enfermedades y proporcionan información sobre la regulación de la biogénesis del ARN.

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