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Distintos circuitos de proteostasis cooperan en el control de la calidad de las proteínas nucleares y citoplasmáticas

Rahul S Samant¹, Christine M Livingston^2,3, Emily M Sontag⁴

¹Department of Biology, Stanford University, Stanford, CA, USA. rsamant@stanford.edu.

|November 16, 2018

Resumen

El control de calidad de la proteína celular (PQC) distingue entre las proteínas citoplasmáticas y nucleares mal plegadas. Las distintas vías de chaperona y ubiquitina aseguran la proteostasis, crucial para prevenir enfermedades como el Alzheimer.

Área de la Ciencia:

Biología molecular
Biología celular
La bioquímica

Sus antecedentes:

El mal plegamiento de proteínas está implicado en enfermedades neurodegenerativas y diabetes.
Los mecanismos de control de calidad de proteínas celulares (PQC) mantienen la proteostasis mediante la eliminación de proteínas mal plegadas.
Las chaperonas moleculares y el sistema ubiquitina-proteasoma son componentes clave de la PQC.

Objetivo del estudio:

Investigar los distintos mecanismos de control de la calidad de las proteínas citoplasmáticas y nucleares.
Definir las funciones de las chaperonas y la ubiquitinación en la limpieza de proteínas mal plegadas en diferentes compartimentos celulares.
Comprender cómo el PQC específico de los organelos contribuye a la integridad del proteoma.

Principales métodos:

Se utilizó un panel de sustratos de PQC con diferentes características y localizaciones.
Análisis de la cooperación entre la chaperona y la ubiquitina ligasa E3 en el aclaramiento de proteínas.
Se investigó el papel de los enlaces específicos de la cadena de la ubiquitina (K48 y K11) en la degradación proteasómica.
Examinó la función de la ubiquilina Dsk2 en el PQC nuclear.

Principales resultados:

La degradación de proteínas mal plegadas en el citoplasma requiere cadenas de ubiquitina vinculadas a K48 y K11, que involucran chaperonas y ligasas E3 específicas.
La degradación de la proteína nuclear mal plegada se basa únicamente en las cadenas de ubiquitina vinculadas a K48, independientemente de los factores específicos de K11.
La proteína ubiquilina Dsk2 se requiere específicamente para limpiar las proteínas nucleares mal plegadas.
Se han definido circuitos distintos de chaperona y ubiquitinación para el PQC citoplasmático y nuclear.

Conclusiones:

El control de calidad de las proteínas citoplasmáticas y nucleares opera a través de mecanismos moleculares distintos.
El reconocimiento combinatorio por las chaperonas y las ligasas E3 dicta la PQC específica de los orgánulos.
Comprender estas distintas vías de PQC es vital para abordar las enfermedades asociadas con la disfunción de la proteostasis.

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