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Hsp70 estabiliza los lisosomas y revierte la patología lisosómica asociada a la enfermedad de Niemann-Pick
Thomas Kirkegaard1, Anke G Roth, Nikolaj H T Petersen
1Apoptosis Department and Centre for Genotoxic Stress Research, Institute of Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen, Denmark.
Nature
|January 30, 2010
Resumen
La proteína de choque térmico 70 (Hsp70) estabiliza los lisosomas al unirse al bis ((monoacilglicero) fosfato (BMP), mejorando la actividad de la esfingomielinasa ácida (ASM). Este hallazgo ofrece nuevos tratamientos potenciales para los trastornos del almacenamiento lisosómico y el cáncer.
Área de la Ciencia:
- Biología celular Biología celular.
- Biología Molecular Biología Molecular
- La bioquímica es la bioquímica.
Sus antecedentes:
- La proteína de choque térmico 70 (Hsp70) es un acompañante molecular crucial para la supervivencia celular bajo estrés.
- La translocación de Hsp70 a los lisosomas sugiere un papel en la función lisosomal y la respuesta al estrés.
- La permeabilización de la membrana lisosómica es un evento clave en la muerte celular inducida por el estrés.
Objetivo del estudio:
- Para dilucidar el mecanismo molecular por el cual Hsp70 estabiliza los lisosomas.
- Para investigar la interacción entre Hsp70 y los componentes lisosómicos.
- Explorar el potencial terapéutico para los trastornos de almacenamiento lisosomal y el cáncer.
Principales métodos:
- Se ha investigado la unión de Hsp70 al bis ((monoacilglicero) fosfato (BMP) en ambientes ácidos.
- Utilizó anticuerpos BMP y mutaciones puntuales Hsp70 (Trp90Phe) para inhibir la interacción Hsp70-BMP.
- Se evaluó el impacto de la inhibición de la interacción Hsp70-BMP y la esfingomielinasa ácida (ASM) en la estabilidad lisosómica.
- Se examinó el efecto de Hsp70 en las células de la enfermedad de Niemann-Pick (NPD) con actividad reducida de ASM.
Principales resultados:
- Hsp70 se une específicamente a BMP en condiciones ácidas, facilitando la unión de BMP y la actividad de ASM.
- La inhibición de la interacción Hsp70-BMP o la actividad ASM revirtió la estabilización lisosómica mediada por Hsp70.
- Las células de pacientes con enfermedad de Niemann-Pick mostraron una disminución de la estabilidad lisosómica debido a la reducción de la actividad de ASM.
- El tratamiento con Hsp70 recombinante corrigió la inestabilidad lisosómica en las células de la enfermedad de Niemann-Pick.
Conclusiones:
- Hsp70 estabiliza los lisosomas a través de la interacción directa con BMP, apoyando la función ASM.
- ASM disfuncional en trastornos de almacenamiento lisosómico como NPD conduce a la inestabilidad lisosómica.
- Hsp70 representa un objetivo terapéutico prometedor para los trastornos de almacenamiento lisosomal y el cáncer.
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