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UBQLN2 Media el aclaramiento del agregado proteico independiente de la autofagia por el proteasoma

Roland Hjerpe¹, John S Bett¹, Matthew J Keuss²

¹Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, Davidson Building, Henry Wellcome Lab of Cell Biology, University of Glasgow, G12 8QQ Glasgow, UK; The MRC Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland.

|August 2, 2016

Resumen

El aclaramiento de proteínas es vital para la supervivencia celular. Una nueva vía utiliza UBQLN2 y HSP70 para eliminar agregados de proteínas a través del proteosoma, con mutaciones que causan neurodegeneración.

Área de la Ciencia:

Biología celular
Mecanismos moleculares de la degradación de las proteínas
La neurociencia

Sus antecedentes:

La homeostasis de las proteínas es crucial para la supervivencia celular.
Las proteínas mal plegadas y agregadas pueden ser tóxicas.
El proteosoma 26S degrada las proteínas ubicuidad, pero existen otras vías.

Objetivo del estudio:

Investigar el papel de los factores de transporte del proteasoma en el aclaramiento del agregado proteico.
Aclarar el mecanismo por el cual UBQLN2 contribuye a la homeostasis de las proteínas.
Para entender el vínculo entre la disfunción UBQLN2 y la neurodegeneración.

Principales métodos:

Se investigó la interacción entre UBQLN2, HSP70 y el proteosoma 26S.
Se ha examinado el aclaramiento de los agregados proteicos en modelos celulares.
Se evaluó el impacto de las mutaciones de UBQLN2 en la unión de chaperonas y el aclaramiento de agregados.
Deficiencias cognitivas estudiadas en modelos de ratón con mutaciones UBQLN2.

Principales resultados:

UBQLN2 actúa con el mecanismo de desagregación HSP70-HSP110 para eliminar los agregados de proteínas a través del proteosoma 26S.
UBQLN2 reconoce el HSP70 ligado al cliente y facilita la degradación de proteínas.
Esta vía de liberación nuclear es distinta de la autofagia.
Las mutaciones humanas de UBQLN2 afectan la unión de la chaperona, el aclaramiento agregado y causan déficits cognitivos en ratones.

Conclusiones:

UBQLN2 media una nueva vía para la eliminación de agregados proteicos en el núcleo.
La disfunción de esta vía mediada por UBQLN2 contribuye a las enfermedades neurodegenerativas.
Dirigirse a esta vía puede ofrecer estrategias terapéuticas para la neurodegeneración.

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