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La traducción de la región 5' no traducida da forma a la respuesta integrada al estrés

Shelley R Starck¹, Jordan C Tsai², Keling Chen³

¹Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA. Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. shelley@walterlab.ucsf.edu nshastri@berkeley.edu peter@walterlab.ucsf.edu.

Science (New York, N.Y.)

|January 30, 2016

Resumen

Este estudio revela que los marcos de lectura abiertos aguas arriba (uORF) en BiP mRNA permiten la traducción durante la respuesta al estrés integrado (ISR). Estos uORF generan péptidos que pueden señalar a las células para el reconocimiento del sistema inmunológico.

Área de la Ciencia:

Biología molecular
Inmunología
Biología celular

Sus antecedentes:

Las regiones traducidas más allá de las secuencias de codificación anotadas son componentes cruciales del proteoma.
Los marcos de lectura abiertos aguas arriba (uORF) en los ARNm bajo el control de la respuesta integrada al estrés (ISR) muestran una traducción privilegiada.
Esta traducción privilegiada se produce a pesar de la inhibición del ARN de transferencia de metionilo iniciador del factor de iniciación eucariota 2-guanosina trifosfato (eIF2·GTP·Met-tRNA)

Objetivo del estudio:

Para medir directamente los productos de traducción uORF durante el ISR.
Investigar el papel de los uORF en la traducción del ARNm BiP durante el estrés celular.
Explorar las posibles implicaciones inmunológicas de los péptidos derivados de la uORF.

Principales métodos:

Desarrollo de un nuevo método, el seguimiento de la traducción por células T, para cuantificar la traducción uORF.
Análisis de los eventos de traducción de uORF en la región 5' no traducida del ARNm BiP.
Investigación del requisito para el factor de iniciación alternativo eIF2A y los uORF no iniciados por AUG en la expresión de BiP.

Principales resultados:

Se identificaron eventos de traducción de la firma de los uORF en el ARNm BiP que no se iniciaron en el codón de inicio de AUG.
Se ha demostrado que la expresión de BiP durante la ISR depende tanto de la eIF2A como de las uORF no iniciadas por AUG.
Se observó una traducción persistente de uORF para varias chaperonas, protegiendo a los ARNm específicos de la ISR.

Conclusiones:

Los uORF no iniciados por AUG y eIF2A son críticos para la traducción de BiP mRNA bajo ISR.
La traducción persistente de uORF puede proteger a los ARNm específicos de la inhibición inducida por la ISR.
La traducción de uORF genera péptidos que pueden servir como ligandos del MHC clase I, marcando potencialmente las células para el reconocimiento inmune adaptativo.

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