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Se requiere el activador mTORC1 SLC38A9 para el eflujo de aminoácidos esenciales de los lisosomas y el uso de

Gregory A Wyant¹, Monther Abu-Remaileh¹, Rachel L Wolfson²

¹Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA.

|October 21, 2017

Resumen

La arginina activa la vía mTORC1 a través de la proteína lisosomal SLC38A9, que también regula la liberación de aminoácidos esenciales de los lisosomas para el crecimiento celular.

Área de la Ciencia:

Biología celular
La bioquímica
Biología molecular

Sus antecedentes:

El objetivo mecanicista del complejo de rapamicina 1 (mTORC1) quinasa es un regulador clave del crecimiento celular, que responde a la disponibilidad de nutrientes.
La detección y el transporte de aminoácidos lisosómicos son críticos para la homeostasis celular, pero los mecanismos subyacentes siguen siendo incompletamente comprendidos.

Objetivo del estudio:

Para aclarar la función de SLC38A9 en la detección de aminoácidos y la activación de mTORC1.
Investigar el papel de SLC38A9 en el transporte de aminoácidos y el metabolismo celular.

Principales métodos:

Validación del SLC38A9 como un sensor de arginina para el mTORC1.
Análisis del transporte mediado por SLC38A9 de aminoácidos esenciales desde los lisosomas.
Evaluación del papel de SLC38A9 en la formación de tumores pancreáticos.

Principales resultados:

SLC38A9 actúa como un sensor de arginina, acoplando la disponibilidad de arginina a la activación de mTORC1.
SLC38A9 facilita el flujo de aminoácidos esenciales, incluida la leucina, desde los lisosomas.
La leucina liberada de los lisosomas a través de SLC38A9 es necesaria para la activación de mTORC1.
Las células de cáncer de páncreas dependen de SLC38A9 para el crecimiento tumoral, utilizando nutrientes macropinocitados.

Conclusiones:

La arginina, a través de SLC38A9, actúa como un mensajero lisosomal para regular la actividad de mTORC1.
SLC38A9 es crucial para la homeostasis de aminoácidos y el crecimiento celular impulsado por nutrientes.
Dirigirse a SLC38A9 puede ofrecer estrategias terapéuticas para los cánceres que dependen de la eliminación de nutrientes.

Palabras clave:

Detección de aminoácidos La autofagia Los lisosomas MTO y MTO La micropinocitosis detección de nutrientes

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