Transcription factor EB: from master coordinator of lysosomal pathways to candidate therapeutic target in degenerative storage diseases

Abstract

The lysosome is the main catabolic hub of the cell. Owing to its role in fundamental processes such as autophagy, plasma membrane repair, mTOR signaling, and maintenance of cellular homeostasis, the lysosome has a profound influence on cellular metabolism and human health. Indeed, inefficient or impaired lysosomal function has been implicated in the pathogenesis of a number of degenerative diseases affecting various organs and tissues, most notably the brain, liver, and muscle. The discovery of the coordinated lysosomal expression and regulation (CLEAR) genetic program and its master controller, transcription factor EB (TFEB), has provided an unprecedented tool to study and manipulate lysosomal function. Most lysosome-based processes-including macromolecule degradation, autophagy, lysosomal exocytosis, and proteostasis-are under the transcriptional control of TFEB. Interestingly, impaired TFEB signaling has been suggested to be a contributing factor in the pathogenesis of several degenerative storage diseases. Preclinical studies based on TFEB exogenous expression to reinstate TFEB activity or promote CLEAR network-based lysosomal enhancement have highlighted TFEB as a candidate therapeutic target for the treatment of various degenerative storage diseases.

Keywords: TFEB; autophagy; degenerative storage diseases; degradative pathways; lysosome enhancement; proteinopathies; transcription factor EB.

Conflict of interest statement

The author declares no conflicts of interest.

© 2016 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.

Figures

Figure 1

TFEB-regulated processes. TFEB positively regulates the transcription of genes involved in all steps of lysosome biogenesis. TFEB promotes lysosomal proliferation, acidification, and exocytosis, and induces genes involved in autophagic pathways. Together, TFEB-modulated processes promote clearance of lysosomal and autophagic substrates.

Figure 2

Regulation of TFEB. Schematic representation of transcriptional and posttranslational regulation of TFEB. TFEB transcription is reinforced by at least two positive loops, one based on TFEB self-induction, and the other based on TFEB-mediated induction of the transcriptional co-activator PGC1α, which in turn promotes TFEB transcription. TFEB transcription is also positively regulated by CREB in competition with the negative regulator FRX. TFEB phosphorylation by mTORC1 triggers TFEB cytosolic retention by 14-3-3 proteins. Dephosphorylation of TFEB by calcineurin promotes TFEB nuclear translocation and activation of the CLEAR network.