The lysosomal GPCR-like protein GPR137B regulates Rag and mTORC1 localization and activity.

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Cell growth is tightly regulated by nutrient-sensing pathways.
• The Rag GTPases and mTORC1 kinase form a key lysosomal signaling complex controlling cell growth.
• Understanding the upstream regulators of this complex is crucial for deciphering cell growth control.

Purpose of the Study:

• To identify novel regulators of the Rag GTPase and mTORC1 signaling pathway.
• To elucidate the function of lysosome-localized proteins in nutrient sensing and cell growth.
• To investigate the role of G protein-coupled receptor (GPCR)-like proteins in lysosomal signaling.

Main Methods:

• Genome-wide human short interfering RNA (siRNA) screen using microscopy.
• Biochemical assays to study protein interactions and localization.
• Cellular and organismal (zebrafish) models to assess functional consequences.

Main Results:

• Discovery of GPR137B, a lysosome-localized GPCR-like protein, as a regulator of Rag GTPases.
• GPR137B enhances Rag localization and activity, promoting mTORC1 translocation and activation, even without amino acids.
• GPR137B controls the dynamic cycle of Rag activation and dissociation from lysosomes, impacting autophagy and lysosome morphology.
• GPR137B deficiency in cells and zebrafish leads to defective autophagy and enlarged lysosomes, similar to Rag-deficient models.

Conclusions:

• GPR137B is a novel lysosomal regulatory protein that acts upstream of the Rag-mTORC1 complex.
• It plays a critical role in nutrient sensing, cell growth, and maintaining lysosome homeostasis.
• GPR137B represents a new target for understanding and potentially modulating cellular growth and metabolic pathways.