Beyond indigestion: emerging roles for lysosome-based signaling in human disease

Abstract

Lysosomes are becoming increasingly recognized as a hub that integrates diverse signals in order to control multiple aspects of cell physiology. This is illustrated by the discovery of a growing number of lysosome-localized proteins that respond to changes in growth factor and nutrient availability to regulate mTORC1 signaling as well as the identification of MiT/TFE transcription factors (MITF, TFEB and TFE3) as proteins that shuttle between lysosomes and the nucleus to elicit a transcriptional response to ongoing changes in lysosome status. These findings have been paralleled by advances in human genetics that connect mutations in genes involved in lysosomal signaling to a broad range of human illnesses ranging from cancer to neurological disease. This review summarizes these new discoveries at the interface between lysosome cell biology and human disease.

Figure 1. Multiple signals converge on the surface of lysosomes to regulate mTORC1 activity

A) Confocal imaging reveals the dramatic recruitment of mTOR (green) to lysosomes (LAMP1, red) following the acute re-feeding (20 minutes) of amino acid starved (2 hours) HeLa cells (scale bar = 10μm, Image provided by Agnes Roczniak-Ferguson). B) This schematic diagram depicts key lysosome localized proteins that coordinate the regulation of mTORC1 activity in response to ongoing changes in nutrient, energy and growth factor availability. Proteins or protein complexes that positively and negatively contribute to mTORC1 activity are shaded green and red respectively. Arrows indicate the actions of specific proteins/protein complexes on their immediate downstream targets (pointed arrows = stimulation of target; blunt arrows = inhibition of target). “AA” indicates sites that have been identified as targets of regulation by amino acid availability.

Figure 2. MiT/TFE transcription factors are regulated by Rag GTPases via both direct and mTORC1-dependent mechanisms

This schematic diagram summarizes the synergistic regulation of MiT/TFE transcription factors by Rag GTPases through both the direct Rag-MiT/TFE interactions that recruit these transcription factors to lysosomes as wells as the role played by the Rags in the activation of mTORC1 and subsequent MiT/TFE phosphorylation. In contrast, mTORC1 targets involved in the regulation of translation and autophagy do not exhibit direct Rag interactions. Green arrows = positive regulation; Red arrows = inhibition.