ZFIN ID: ZDB-PUB-190501-6
The lysosomal GPCR-like protein GPR137B regulates Rag and mTORC1 localization and activity
Gan, L., Seki, A., Shen, K., Iyer, H., Han, K., Hayer, A., Wollman, R., Ge, X., Lin, J.R., Dey, G., Talbot, W.S., Meyer, T.
Date: 2019
Source: Nature cell biology   21(5): 614-626 (Journal)
Registered Authors: Meyer, Tobias, Talbot, William S.
Keywords: none
MeSH Terms:
  • Animals
  • Autophagy/genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics*
  • Gene Expression Regulation/genetics
  • Genome, Human/genetics*
  • Humans
  • Lysosomes/genetics
  • Mechanistic Target of Rapamycin Complex 1/genetics
  • Microglia/metabolism
  • Monomeric GTP-Binding Proteins/genetics*
  • Multiprotein Complexes/chemistry
  • Multiprotein Complexes/genetics
  • RNA, Small Interfering/genetics
  • Receptors, G-Protein-Coupled/antagonists & inhibitors
  • Receptors, G-Protein-Coupled/genetics*
  • Zebrafish/genetics
  • Zebrafish/growth & development
PubMed: 31036939 Full text @ Nat. Cell Biol.
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.