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Los híbridos de ARN-ADN citoplasmáticos derivados del bucle R activan una respuesta inmune

Magdalena P Crossley¹, Chenlin Song¹, Michael J Bocek¹

¹Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA.

|December 21, 2022

Resumen

Los bucles R, híbridos de ARN-ADN, pueden desencadenar respuestas inmunes innatas cuando se procesan mal y se acumulan en el citoplasma. Esta acumulación aberrante conduce a la muerte celular, contribuyendo potencialmente a enfermedades como el cáncer y la neurodegeneración.

Área de la Ciencia:

Biología molecular
La genética
Inmunología

Sus antecedentes:

Los bucles R son estructuras cruciales de ácido nucleico involucradas en los procesos celulares.
La desregulación de la dinámica del bucle R está relacionada con el daño del ADN y la inestabilidad del genoma.
El papel de las endonucleasas como XPG en el procesamiento del bucle R y sus consecuencias no estaban claras.

Objetivo del estudio:

Identificar y caracterizar una nueva población de híbridos de ARN y ADN citoplasmáticos.
Para aclarar los mecanismos de procesamiento del bucle R y la formación de híbridos citoplasmáticos.
Investigar las consecuencias celulares del procesamiento aberrante del bucle R, incluida la activación inmune y la muerte celular.

Principales métodos:

Perturbación de los circuitos R nucleares por agotamiento de la senataxina (SETX) o el BRCA1.
Identificación de los híbridos citoplasmáticos de ARN y ADN.
Evaluación de la unión de los híbridos a los receptores de reconocimiento de patrones (cGAS, TLR3).
Monitoreo de la activación del IRF3 y la inducción de la apoptosis.
Análisis de células derivadas de pacientes con mutaciones SETX o BRCA1.

Principales resultados:

Se identificó una nueva población de híbridos de ARN-ADN citoplasmáticos como productos de procesamiento de bucle R.
La formación híbrida citoplasmática fue dependiente de XPG y XPF.
Estos híbridos se originan en bucles R nucleares específicos.
Los híbridos citoplasmáticos activan la respuesta inmune innata a través de cGAS y TLR3, lo que lleva a la activación de IRF3 y la apoptosis.
El procesamiento del bucle R y la activación inmune se observaron en células de pacientes con ataxia y en células cancerosas con mutación BRCA1.

Conclusiones:

Los híbridos de ARN-ADN pueden ser inmunogénicos cuando se procesan de manera aberrante y se acumulan en el citoplasma.
El procesamiento del bucle R contribuye a la muerte celular a través de la activación inmune innata.
El procesamiento aberrante del bucle R y la activación inmune pueden desempeñar un papel en la neurodegeneración y el cáncer.

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