Reference

EMBO Rep. 2019 Dec 5;20(12):e47964. doi: 10.15252/embr.201947964. Epub
2019 Nov 3EMBOR PORTADA.

Authors

Manuel Martín-Expósito, María Eugenia Gas, Nada Mohamad, Carmen Nuño-Cabanes, Ana Tejada-Colón, Pau Pascual-García, Lorena de la Fuente, Belén Chaves-Arquero, Jonathan Merran, Jeffry Corden , Ana Conesa, José Manuel Pérez-Cañadillas, Jerónimo Bravo, Susana Rodríguez-Navarro.

Abstract

RNA-binding proteins (RBPs) participate in all steps of gene expression, underscoring their potential as regulators of RNA homeostasis. We structurally and functionally characterize Mip6, a four-RNA recognition motif (RRM)-containing RBP, as a functional and physical interactor of the export factor Mex67. Mip6-RRM4 directly interacts with the ubiquitin-associated (UBA) domain of Mex67 through a loop containing tryptophan 442. Mip6 shuttles between the nucleus and the cytoplasm in a Mex67-dependent manner and concentrates in cytoplasmic foci under stress. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation experiments show preferential binding of Mip6 to mRNAs regulated by the stress-response Msn2/4 transcription factors. Consistent with this binding, MIP6 deletion affects their export and expression levels.
Additionally, Mip6 interacts physically and/or functionally with proteins with a role in mRNA metabolism and transcription such as Rrp6, Xrn1, Sgf73, and Rpb1. These results reveal a novel role for
Mip6 in the homeostasis of Msn2/4-dependent transcripts through its direct interaction with the Mex67 UBA domain.

Description

Las células se encuentran sometidas a situaciones cambiantes en su entorno que las estresan, lo que las obliga a ajustar su funcionamiento para sobrevivir. Se trata de un proceso esencial que deben reajustar con mucha precisión mediante modificaciones en la expresión de sus genes, sintetizando nuevos ARNs. Estos ARNs son necesarios para la síntesis de proteínas que ayudan a la célula a soportar el estrés. Mip6, proteína de función desconocida encontrada en el organismo modelo S. cerevisiae, es capaz de unirse a ARNs inducibles por estrés y modular su cantidad, de manera que ayuda a la célula a responder al estrés. Además, Mip6 se acumula en gránulos de estrés, estructuras producidas bajo condiciones no óptimas que han sido relacionadas previamente con enfermedades como la esclerosis lateral amiotrófica o la demencia frontotemporal. También hemos podido determinar los elementos clave que permiten la interacción de Mip6 no sólo con ARNs, sino también con la proteína Mex67, cuya función es esencial para la supervivencia de todas las células eucariotas, lo que supone un gran avance en su descripción estructural. Los resultados de este trabajo revelan el papel de Mip6 en modular la cantidad de ARNs sintetizados en condiciones de estrés a través de su interacción con Mex67.

 

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REFERENCIA DEL GRUPO INVESTIGADOR

La Unidad de Expresión Génica y Metabolismo del RNA dirigido por la Dra. Susana Rodríguez Navarro en el Instituto de Biomedicina de Valencia (IBV-CSIC) está centrada en entender los mecanismos moleculares que son responsables de la coordinación de las distintas etapas de la expresión génica y su posible relación con enfermedades humanas. Más específicamente y utilizando como modelo la levadura S.
cerevisiae, analiza el papel biológico de una serie de complejos y proteínas conservadas evolutivamente para las que se han descrito funciones esenciales en procesos de epigenética y transcripción (Complejo SAGA), y en la exportación y metabolismo del RNA (Complejo TREX-2).

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