Rap1-GTPases control mTORC1 activity by coordinating lysosome organization with amino acid availability

Anders P Mutvei,John Blenis,Jens C Hamann,Sang Gyun Kim,Michal J Nagiec,C Theresa Vincent

doi:10.1038/s41467-020-15156-5

Anders P Mutvei, John Blenis + Show 4 more

Open Access

https://doi.org/10.1038/s41467-020-15156-5

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Abstract

The kinase mTOR complex 1 (mTORC1) promotes cellular growth and is frequently dysregulated in cancers. In response to nutrients, mTORC1 is activated on lysosomes by Rag and Rheb guanosine triphosphatases (GTPases) and drives biosynthetic processes. How limitations in nutrients suppress mTORC1 activity remains poorly understood. We find that when amino acids are limited, the Rap1-GTPases confine lysosomes to the perinuclear region and reduce lysosome abundance, which suppresses mTORC1 signaling. Rap1 activation, which is independent of known amino acid signaling factors, limits the lysosomal surface available for mTORC1 activation. Conversely, Rap1 depletion expands the lysosome population, which markedly increases association between mTORC1 and its lysosome-borne activators, leading to mTORC1 hyperactivity. Taken together, we establish Rap1 as a critical coordinator of the lysosomal system, and propose that aberrant changes in lysosomal surface availability can impact mTORC1 signaling output.

Highlights

The kinase mTOR complex 1 promotes cellular growth and is frequently dysregulated in cancers
When cells are supplied with nutrients, mTOR complex 1 (mTORC1) is recruited to lysosomes and late endosomes where it is activated and promotes various biosynthetic processes, including protein, nucleotide and lipid synthesis3. mTORC1 activation is mediated by Rag-guanosine triphosphatases (GTPases), which recruit and anchor mTORC1 to the lysosomal surface where the RhebGTPase stimulates its phosphotransferase activity[3,4,5]
Consistent with the increased abundance of lysosomes observed upon Rap[1] depletion, we isolated considerably more RagC associated with lysosome-enriched membranes from Rap1-depleted cells compared to control cells (Fig. 5b), further arguing that these cells contain more RagC-associated lysosomes. These results indicate that Rap[1] controls the cellular capacity for mTORC1 activation: when Rap[1] activity is increased during limitations in amino acids, the total lysosomal surface area decreases, and as a consequence so does mTORC1 activity

Summary

Introduction

The kinase mTOR complex 1 (mTORC1) promotes cellular growth and is frequently dysregulated in cancers. We find that when amino acids are limited, the Rap1-GTPases confine lysosomes to the perinuclear region and reduce lysosome abundance, which suppresses mTORC1 signaling. Rap[1] activation, which is independent of known amino acid signaling factors, limits the lysosomal surface available for mTORC1 activation. The mTOR complex 1 (mTORC1) protein kinase integrates nutrient signals to drive cellular growth and is dysregulated in multiple diseases, including cancer[1,2]. We report that when amino acids are limited, the Rap1-GTPases concentrate lysosomes to the perinuclear region and reduce overall lysosome abundance, which suppresses mTORC1 signaling. This is due to a Rap1-mediated decrease in the surface available for mTORC1 activation. We propose that aberrant changes in lysosome abundance impact overall mTORC1 signaling output

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