The Lysosome at the Intersection of Cellular Growth and Destruction

Abstract

The lysosome is an essential catabolic organelle that consumes cellular biomass to regenerate basic building blocks that can fuel anabolic reactions. This simple view has evolved more recently to integrate novel functions of the lysosome as a key signaling center, which can steer the metabolic trajectory of cells in response to changes in nutrients, growth factors, and stress. Master protein kinases and transcription factors mediate the growth-promoting and catabolic activities of the lysosome and undergo a complex interplay that enables cellular adaptation to ever-changing metabolic conditions. Understanding how this coordination occurs will shed light on the fundamental logic of how the lysosome functions to control growth in the context of development, tissue homeostasis, and cancer.

Keywords: TFEB; anabolism; autophagy; catabolism; lysosome; mTORC1; nutrient sensing.

Figure1:. Pro- and anti-growth properties of the lysosome

The lysosome is characterized by its low pH (ranging between 4.5 and 5.5), which is mainly established by the vacuolar H⁺ ATPases (v-ATPases)-dependent pumping of protons from the cytosol into the lysosomal lumen, aided by the import of anions and antiport of cations which neutralize imbalance in ionic charges and allow further proton transport. The internal acidic environment is critical for the activity of luminal proteases, lipases and ribonucleases that degrade incoming macromolecular substrates. Lysosomal membrane proteins include permeases that transport amino acids, sugars, lipids and ions across the limiting membrane. The limiting membrane functions as a platform for the assembly of a macromolecular complex centered on the mTORC1 protein kinase, which translates nutrient and growth factor abundance into metabolic instructions via downstream effectors such as the TFEB transcription factor. Lysosomes are the end point for multiple trafficking routes, including endocytic and scavenging pathways. Endosome-lysosome fusion can either promote the breakdown and utilization of extracellular nutrients (pro-growth), or the degradation and silencing of signaling receptors (anti-growth). The lysosome also fuses with autophagosome as part of the autophagy process for the degradation of intracellular constituents. Building blocks generated by lysosomal degradation are either stored inside the lysosomes or transported to the cytoplasm. Lysosomes also engage in direct interactions with other organelles such as mitochondria, endoplasmic reticulum and lipid droplets via specialized structures known as membrane contact sites.

Figure2:. Regulation of mTORC1 signaling pathways

The growth-promoting role of the lysosome emerged from its identification as the cellular platform for the activation of the master growth regulator, mTORC1 kinase. A coincidence detection mechanism ensures that the kinase activity of mTORC1 is turned on at the lysosomal limiting membrane only when both nutrients and growth factors are plentiful. Nutrient signals converge on the Rag GTPases, whereas growth factor signals converge on Rheb GTPase. (A) Under low nutrient conditions the Rag GTPases, which are anchored to the lysosomal membrane by the Ragulator/Lamtor complex, are in the inactive state, in which RagA/B is GDP loaded and RagC/D is GTP loaded. Inactive Rag GTPases cannot bind to mTORC1, which remains inactive in the cytosol. In low nutrients GATOR1, the GTPase-activating protein (GAP) for RagA/B, promotes the accumulation of GDP-bound RagA/B, thereby blocking the recruitment of mTORC1. When growth factors are absent the tuberous sclerosis complex (TSC), which functions as GAP toward Rheb, catalyzes the conversion from the active GTP-bound Rheb to inactive GDP-bound form. (B) In response to nutrients and growth factors, respectively, GATOR1 and TSC become inactive, thus promoting the transition of RagA/B and Rheb, respectively, to the GTP bound form. GTP-loaded RagA/B then physically recruits mTORC1 to the lysosomal membrane, whereas GTP-loaded Rheb promotes mTORC1 kinase activation. Cytoplasmic pools of leucine, arginine and methionine signal to the Rag GTPases via their dedicated sensors, Sestrin1/2, CASTOR1/2 and SAMTOR, respectively. Amino acid abundance within the lysosomal lumen, particularly arginine, is detected by the SLC38A9 amino acid permease. mTORC1 activation by cholesterol also requires SLC38A9 in a manner that is separable from its arginine sensing function. Oxysterol binding protein (OSBP) transfer cholesterol from ER to the lysosomal membrane, thus favoring mTORC1 activation. The lysosomal cholesterol transporter NPC1 negatively regulates cholesterol-mTORC1 signaling by promoting export of cholesterol to acceptor compartments, such as ER, Golgi and plasma membrane. Inactive mTORC1 is shown in grey and active mTORC1 is in yellow. Positive regulators of the mTORC1 pathways are in green, while negative regulators of mTORC1 are shown in red.