2. Academic Validation
  3. The lysosomal GPCR-like protein GPR137B regulates Rag and mTORC1 localization and activity

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

  • Nat Cell Biol. 2019 May;21(5):614-626. doi: 10.1038/s41556-019-0321-6.
Lin Gan # 1,  Akiko Seki # 1,  Kimberle Shen 2,  Harini Iyer 2,  Kyuho Han 1,  Arnold Hayer 1,  Roy Wollman 3,  Xuecai Ge 1,  Jerry R Lin 1,  Gautam Dey 1,  William S Talbot 2,  Tobias Meyer 4
Affiliations

Affiliations

  • 1 Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA.
  • 2 Department of Developmental Biology, Stanford University, Stanford, CA, USA.
  • 3 Department of Integrative Biology and Physiology and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
  • 4 Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA. [email protected].
  • # Contributed equally.
PMID: 31036939 DOI: 10.1038/s41556-019-0321-6
Abstract

Cell growth is controlled by a lysosomal signalling complex containing Rag small GTPases and mammalian target of rapamycin complex 1 (mTORC1) kinase. Here, we carried out a microscopy-based genome-wide human short interfering RNA screen and discovered a lysosome-localized G protein-coupled receptor (GPCR)-like protein, GPR137B, that interacts with Rag GTPases, increases Rag localization and activity, and thereby regulates mTORC1 translocation and activity. High GPR137B expression can recruit and activate mTORC1 in the absence of Amino acids. Furthermore, GPR137B also regulates the dissociation of activated Rag from lysosomes, suggesting that GPR137B controls a cycle of Rag activation and dissociation from lysosomes. GPR137B-knockout cells exhibited defective Autophagy and an expanded lysosome compartment, similar to Rag-knockout cells. Like zebrafish RagA mutants, GPR137B-mutant zebrafish had upregulated TFEB target gene expression and an expanded lysosome compartment in microglia. Thus, GPR137B is a GPCR-like lysosomal regulatory protein that controls dynamic Rag and mTORC1 localization and activity as well as lysosome morphology.

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