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La pequeña molécula se dirige a TMED9 y promueve la degradación lisosómica para revertir la proteinopatía

Moran Dvela-Levitt¹, Maria Kost-Alimova², Maheswarareddy Emani¹

¹Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

|July 27, 2019

Resumen

Una nueva molécula pequeña, BRD4780, elimina los agregados de proteínas tóxicas de la enfermedad renal de Mucina 1 (MKD) al dirigirse al receptor TMED9. Este descubrimiento ofrece una estrategia terapéutica prometedora para MKD y otras proteinopatías.

Área de la Ciencia:

Nefrología
Biología molecular
La bioquímica

Sus antecedentes:

Las proteinopatías tóxicas son el resultado de la acumulación de proteínas intracelulares mal plegadas, que carecen de tratamientos específicos.
La enfermedad renal por mucina 1 (MKD) es causada por una mutación de desplazamiento de marco del gen MUC1 (MUC1-fs), que conduce a una acumulación intracelular tóxica.
La vía de respuesta a la proteína desplegada ATF6 (UPR) se activa por la acumulación de MUC1-fs.

Objetivo del estudio:

Identificar estrategias terapéuticas para la enfermedad renal de Mucin 1.
Investigar el mecanismo de acumulación y aclaramiento intracelular de MUC1-fs.
Para explorar el papel de los receptores de carga en el tráfico de proteínas mal plegadas.

Principales métodos:

Detección de moléculas pequeñas que eliminan el MUC1-fs.
Utilizando células derivadas de pacientes, modelos de ratones knockin y organoides renales.
Investigando la interacción entre BRD4780, MUC1-fs y el receptor de carga TMED9.

Principales resultados:

BRD4780 elimina efectivamente el MUC1-fs de las células del paciente, los riñones del ratón y los organoides.
MUC1-fs es secuestrado en vesículas que contienen TMED9 dentro de la vía secretora temprana.
BRD4780 se une a TMED9, liberando MUC1-fs para la degradación lisosómica, imitando los efectos de deleción de TMED9.

Conclusiones:

BRD4780 es un promedio terapéutico prometedor para la enfermedad renal de Mucin 1.
El estudio revela un nuevo mecanismo de atrapamiento de proteínas mal plegadas por los receptores de carga.
Dirigirse a TMED9 ofrece una estrategia para liberar y degradar proteínas mal plegadas en proteinopatías tóxicas.

Palabras clave:

Las vesículas COP Estrés en las urgencias El aparato de Golgi receptor de carga El retículo endoplasmático células epiteliales el riñón Productos orgánicos vía secretora Respuesta proteica desdoblada

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