A Gene Network Regulating Lysosomal Biogenesis and Function

  title={A Gene Network Regulating Lysosomal Biogenesis and Function},
  author={Marco Sardiello and Michela Palmieri and Alberto di Ronza and Diego Luis Medina and Marta Valenza and Vincenzo Alessandro Gennarino and Chiara Di Malta and Francesca Donaudy and Valerio Embrione and Roman S. Polishchuk and Sandro Banfi and Giancarlo Parenti and Elena Cattaneo and Andrea Ballabio},
  pages={473 - 477}
Master Controller Cellular organelles allow the localized regulation of specialized processes. Under certain conditions, such as increased growth, organelles may be required to alter their function. Coordinated regulation of the gene networks required for mitochondrial and endoplasmic reticulum function has been observed. Now, Sardiello et al. (p. 473; published online 25 June) have discovered a gene network regulating the lysosome, the major organelle involved in the degradation of… 
Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways.
This analysis revealed a comprehensive system regulating the expression, import and activity of lysosomal enzymes that control the degradation of proteins, glycosaminoglycans, sphingolipids and glycogen, and provides potential therapeutic targets to modulate cellular clearance in a variety of disease conditions.
Lysosomes as dynamic regulators of cell and organismal homeostasis
The modulation of lysosome function could be a promising therapeutic strategy for the treatment of cancer as well as metabolic and neurodegenerative disorders.
Lysosome biogenesis in health and disease
TFEB‐mediated enhancement of lysosomal biogenesis is highlighted and function as a candidate strategy to counteract the progression of these diseases.
Endocytic regulation of cellular ion homeostasis controls lysosome biogenesis
Exo-endocytosis of a Na + /H + exchanger controls lysosome biogenesis through Ca 2+ /calcineurin-mediated activation of TFEB in response to osmotic stress to promote the turnover of toxic proteins and cell survival.
Transcription factor EB: from master coordinator of lysosomal pathways to candidate therapeutic target in degenerative storage diseases
  • M. Sardiello
  • Biology
    Annals of the New York Academy of Sciences
  • 2016
Interestingly, impaired TFEB signaling has been suggested to be a contributing factor in the pathogenesis of several degenerative storage diseases and is highlighted as a candidate therapeutic target for the treatment of various degenerative diseases.
TFEB and the CLEAR network.
The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis
TFEB is identified as a target of mTOR and a mechanism for matching the transcriptional regulation of genes encoding proteins of autophagosomes and lysosomes to cellular need is suggested.
The Nutrient-Responsive Transcription Factor TFE3 Promotes Autophagy, Lysosomal Biogenesis, and Clearance of Cellular Debris
The identification of transcription factor E3 (TFE3) as another regulator of lysosomal homeostasis that induced expression of genes encoding proteins involved in autophagy and lYSosomal biogenesis in ARPE-19 cells in response to starvation and lysOSomal stress is reported.
The cellular pathology of lysosomal diseases
The cryptic evolution of events leading to irreversible changes may be dissociated from the cellular storage phenotype, as revealed by the outcome of therapeutic gene transfer undertaken at different stages of disease.
The gene for the lysosomal protein LAMP3 is a direct target of the transcription factor ATF4
Results reveal that ATF4 directly regulates LAMP3, the first identification of a gene for a lysosomal component whose expression is directly controlled by ATF4, and may provide a key link between stresses such as accumulation of unfolded proteins and modulation of autophagy, which removes them.


Lysosomal biogenesis in lysosomal storage disorders.
The coordination of these events in lysosomal biogenesis would suggest that a common mechanism(s) may be in operation in storage disorder-affected skin fibroblasts; both of these systems result in an increase in the size and the number of lysOSomal vacuoles.
Proteomics of the lysosome.
Helix-Loop-Helix Proteins: Regulators of Transcription in Eucaryotic Organisms
The helix-loop-helix (HLH) family of transcriptional regulatory proteins are key players in a wide array of developmental processes, including neurogenesis, myogenesis, hematopoiesis, and pancreatic development and the structure and functional properties are examined.
NCU-G1 is a highly glycosylated integral membrane protein of the lysosome.
The lysosomal localization of the mouse orthologue of the human C1orf85 protein has been demonstrated, which has been termed kidney-predominant protein NCU-G1 (GenBank accession number: AB027141), which encodes a 404 amino acid protein with a calculated molecular mass of 39 kDa.
Systemic inflammation and neurodegeneration in a mouse model of multiple sulfatase deficiency
Sumf1−/− mice showed a generalized inflammatory process characterized by a massive presence of highly vacuolated macrophages, which are the main site of lysosomal storage, and a strong increase in the expression levels of inflammatory cytokines and of apoptotic markers in both the CNS and liver demonstrated that inflammation and apoptosis occur at the late stage of disease.
Lysosomal Activation Is a Compensatory Response Against Protein Accumulation and Associated Synaptopathogenesis—An Approach for Slowing Alzheimer Disease?
  • J. Bendiske, B. Bahr
  • Biology, Chemistry
    Journal of neuropathology and experimental neurology
  • 2003
Data indicate that compensatory activation of lysosomes follows protein accumulation events, and that lysOSomal modulation represents a novel approach for treating Alzheimer disease and other protein deposition diseases.
The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1
It is found that the Rag proteins—a family of four related small guanosine triphosphatases (GTPases)—interact with mTORC1 in an amino acid–sensitive manner and are necessary for the activation of the m TORC1 pathway by amino acids.
Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking
It is reported that a Beclin1-binding autophagic tumour suppressor, UVRAG, interacts with the class C Vps complex, a key component of the endosomal fusion machinery, and this interaction stimulates Rab7 GTPase activity and autophagosome fusion with late endosomes/lysosomes, thereby enhancing delivery and degradation of Autophagic cargo.