title: Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways.
abstract: In metazoans, lysosomes are the center for the degradation of macromolecules and play a key role in a variety of cellular processes, such as autophagy, exocytosis and membrane repair. Defects of lysosomal pathways are associated with lysosomal storage disorders and with several late onset neurodegenerative diseases. We recently discovered the CLEAR (Coordinated Lysosomal Expression and Regulation) gene network and its master gene transcription factor EB (TFEB), which regulates lysosomal biogenesis and function. Here, we used a combination of genomic approaches, including ChIP-seq (sequencing of chromatin immunoprecipitate) analysis, profiling of TFEB-mediated transcriptional induction, genome-wide mapping of TFEB target sites and recursive expression meta-analysis of TFEB targets, to identify 471 TFEB direct targets that represent essential components of the CLEAR network. 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. Interestingly, the CLEAR network appears to be involved in the regulation of additional lysosome-associated processes, including autophagy, exo- and endocytosis, phagocytosis and immune response. Furthermore, non-lysosomal enzymes involved in the degradation of essential proteins such as hemoglobin and chitin are also part of the CLEAR network. Finally, we identified nine novel lysosomal proteins by using the CLEAR network as a tool for prioritizing candidates. This study provides potential therapeutic targets to modulate cellular clearance in a variety of disease conditions.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.
authors.forename: Michela
authors.initials: M
authors.lastname: Palmieri
authors.forename: Soren
authors.initials: S
authors.lastname: Impey
authors.forename: Hyojin
authors.initials: H
authors.lastname: Kang
authors.forename: Alberto
authors.initials: A
authors.lastname: di Ronza
authors.forename: Carl
authors.initials: C
authors.lastname: Pelz
authors.forename: Marco
authors.initials: M
authors.lastname: Sardiello
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D011506:Proteins; C064972:TFEB protein, human