Novel roles for the MiTF/TFE family of transcription factors in organelle biogenesis, nutrient sensing, and energy homeostasis

Abstract

The MiTF/TFE family of basic helix-loop-helix leucine zipper transcription factors includes MITF, TFEB, TFE3, and TFEC. The involvement of some family members in the development and proliferation of specific cell types, such as mast cells, osteoclasts, and melanocytes, is well established. Notably, recent evidence suggests that the MiTF/TFE family plays a critical role in organelle biogenesis, nutrient sensing, and energy metabolism. The MiTF/TFE family is also implicated in human disease. Mutations or aberrant expression of most MiTF/TFE family members has been linked to different types of cancer. At the same time, they have recently emerged as novel and very promising targets for the treatment of neurological and lysosomal diseases. The characterization of this fascinating family of transcription factors is greatly expanding our understanding of how cells synchronize environmental signals, such as nutrient availability, with gene expression, energy production, and cellular homeostasis.

Fig. 1

Mechanism of TFEB regulation by Rag GTPases. In fully fed cells, TFEB is recruited to lysosomes via direct interaction with active Rag GTPases. This recruitment is critical for mTORC1-dependent phosphorylation and the subsequent 14-3-3-mediated retention of TFEB in the cytosol. Inactivation of Rags and mTORC1 following starvation leads to dissociation of the TFEB/14-3-3 complex and rapid translocation of TFEB to the nucleus. The same regulatory mechanism controls the activity and intracellular distribution of TFE3

Fig. 2

Model of TFEB function and regulation in different cell types. a TFEB plays a critical role in the adaptation of cells to nutrient deprivation. In hepatocytes, TFEB translocates to the nucleus under starvation conditions to promote autophagy, lysosomal biogenesis, and expression of key metabolic regulators, thus ensuring efficient use of energy stores and cell survival. A TFEB auto-regulatory feedback loop (pink arrow) results in increased TFEB levels under prolonged starvation conditions. b Activation of TFEB in osteoclasts is not dependent on nutrient levels but on RANKL-mediated signaling. Up-regulation of specific lysosomal genes by TFEB is essential for resorption of the bone matrix. c The role of TFEB in the cellular response to starvation is evolutionary conserved. In Caenorhabditis elegans, HLH-30 accumulates in the nucleus upon fasting and up-regulates expression of genes that mediate lipophagy. Starvation-induced activation of HLH-30 may also have important consequences in longevity

Fig. 3

The MiTF/TFE family of transcription factors regulates multiple cellular processes. The members of the MiTF/TFE family share critical roles in organelle biogenesis, cell survival and differentiation, and tumorigenesis. In addition, TFEB and TFE3 participate in the regulation of nutrient sensing, energy metabolism, and cellular clearance