Lysosomal adaptation: how the lysosome responds to external cues - PubMed (original) (raw)

Lysosomal adaptation: how the lysosome responds to external cues

Carmine Settembre et al. Cold Spring Harb Perspect Biol. 2014.

Abstract

Recent evidence indicates that the importance of the lysosome in cell metabolism and organism physiology goes far beyond the simple disposal of cellular garbage. This dynamic organelle is situated at the crossroad of the most important cellular pathways and is involved in sensing, signaling, and transcriptional mechanisms that respond to environmental cues, such as nutrients. Two main mediators of these lysosomal adaptation mechanisms are the mTORC1 kinase complex and the transcription factor EB (TFEB). These two factors are linked in a lysosome-to-nucleus signaling pathway that provides the lysosome with the ability to adapt to extracellular cues and control its own biogenesis. Modulation of lysosomal function by acting on TFEB has a profound impact on cellular clearance and energy metabolism and is a promising therapeutic target for a large variety of disease conditions.

Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

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Figures

Figure 1.

Figure 1.

The lysosome and cellular clearance. The figure depicts the three major aspects of lysosome-mediated cellular clearance: cargo targeting to lysosomes, substrate degradation, and secretion. Lysosomes receive extracellular material via endocytosis and intracellular material via autophagy. In these processes, lysosomes fuse with late endosomes and with autophagosomes, respectively. Subsequently, substrates are degraded by lysosomal hydrolases and the resulting breakdown products are used to generate new cellular components and energy in response to the nutritional needs of the cell. Lysosomes also undergo Ca2+-regulated exocytosis to secrete their content into the extracellular space and to repair damaged plasma membranes.

Figure 2.

Figure 2.

Identification of the CLEAR gene network. A systems biology approach was used to test the hypothesis that lysosomal genes are coregulated. The analysis of the expression behavior of genes encoding lysosomal proteins was analyzed using publicly available microarray data and revealed that they are coexpressed. Pattern discovery analysis revealed the presence of a palindromic 10-base site in the promoters of known lysosomal genes. This sequence was previously identified as a specific version of a known target site for basic helix–loop–helix (bHLH) transcription factors, also known as an E-box. Thus, these two independent approaches—namely, coexpression and promoter analyses—identified a new gene network that was named CLEAR (coordinated lysosomal expression and regulation). envir., environment.

Figure 3.

Figure 3.

The LYNUS machinery. A complex machinery, made of several interacting protein complexes was identified on the lysosomal surface. This machinery, herein named lysosomal nutrient sensing (LYNUS), includes regulatory proteins associated with mTOR, such as RAPTOR (regulatory-associated protein of mTOR), mLST8 (mammalian lethal with SEC13 protein), and DEPTOR (DEP domain-containing mTOR-interacting protein), and Rag GTPases (RagA or RagB and RagC or RagD), which activate mTORC1 on the lysosomal surface. A complex known as Ragulator mediates the activation and docking of Rag GTPases to the lysosomal membrane. The small GTPase Ras homolog enriched in brain (Rheb) is also involved in the growth factor-mediated activation of mTORC1. The V-ATPase complex functions in amino acid sensing and mediates amino acid-sensitive interactions between Rag GTPases and Ragulator, which is the initial step in lysosomal signaling. The endolysosomal ATP-sensitive Na+-permeable channel (lysoNaATP), which comprises the subunits two pore calcium channel 1 (TPC1) and TPC2, is located on the lysosomal membrane, and it has recently been shown to interact with mTORC1 and to participate in nutrient sensing. (Figure is based on data from Settembre et al. 2013b.)

Figure 4.

Figure 4.

Model of TFEB regulation and function during starvation. This model illustrates how TFEB mediates the starvation response by regulating lipid catabolism. In the presence of sufficient nutrients, TFEB interacts with the LYNUS machinery, which senses lysosomal nutrient levels via the vacuolar ATPase (V-ATPase) complex, and is phosphorylated by mammalian target of rapamycin complex 1 (mTORC1) on the lysosomal surface (1). This keeps TFEB inactive by cytosolic sequestration. During starvation, mTORC1 is released from the LYNUS machinery and becomes inactive. Thus, TFEB can no longer be phosphorylated by mTORC1 and translocates to the nucleus, where it induces its own transcription (2). Therefore, starvation regulates TFEB activity through a dual mechanism that involves a posttranslational modification (that is, phosphorylation) and a transcriptional autoregulatory loop. Once in the nucleus, TFEB regulates the expression of genes involved in the lysosomal–autophagy pathway (3), as well as of _Ppar_-α (peroxisome proliferator-activated receptor-α) and _Pgc_-1α (PPAR-γ coactivator 1α) and their target genes (4). In this way, TFEB controls the starvation response by activating both lipophagy (5) and fatty acid β-oxidation (6). (Figure is based on data from Settembre et al. 2013a,.)

Figure 5.

Figure 5.

TFEB as a tool to promote cellular clearance in human disease. Human diseases for which viral-mediated TFEB-overexpression-induced cellular clearance and ameliorated disease phenotype in mouse models.

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