TFE3 protein (Transcription Factor Binding to IGHM Enhancer 3) is a basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor encoded by the [TFE3](/genes/tfe3) gene. As a member of the MiT/TFE family alongside [TFEB](/genes/tfeb) and [MITF](/genes/mitf), TFE3 functions as a master regulator of lysosomal biogenesis, [autophagy](/entities/autophagy), and cellular stress responses by binding Coordinated Lysosomal Expression and Regulation (CLEAR) elements in target gene promoters. Its nuclear-cytoplasmic shuttling is controlled by [mTORC1](/genes/mtor)-dependent phosphorylation, and disruption of this regulation contributes to lysosomal dysfunction in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and [Huntington's disease](/diseases/huntington-disease).
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TFE3 Protein
Overview
TFE3 protein (Transcription Factor Binding to IGHM Enhancer 3) is a basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor encoded by the [TFE3](/genes/tfe3) gene. As a member of the MiT/TFE family alongside [TFEB](/genes/tfeb) and [MITF](/genes/mitf), TFE3 functions as a master regulator of lysosomal biogenesis, [autophagy](/entities/autophagy), and cellular stress responses by binding Coordinated Lysosomal Expression and Regulation (CLEAR) elements in target gene promoters. Its nuclear-cytoplasmic shuttling is controlled by [mTORC1](/genes/mtor)-dependent phosphorylation, and disruption of this regulation contributes to lysosomal dysfunction in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and [Huntington's disease](/diseases/huntington-disease).
AAV-TFE3 gene therapy in dopaminergic neurons attenuates α-synuclein toxicity in rat PD models
Huntington's Disease
Mutant [huntingtin](/proteins/huntingtin-protein) physically sequesters TFE3 in cytoplasmic aggregates
TFE3 activation through trehalose or mTORC1 inhibition reduces polyQ aggregation
Combined TFEB/TFE3 double activation clears mutant [huntingtin](/proteins/huntingtin) more effectively than single activation
Lysosomal Storage Disorders with Neurodegeneration
TFE3 is constitutively activated in Pompe disease, Gaucher disease, [Niemann-Pick C](/diseases/niemann-pick-disease), and other LSDs — reflecting compensatory lysosomal biogenesis. Additional TFE3 activation via gene therapy can augment this response.
[Martina JA et al., The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris (2014) (2014)](https://doi.org/10.1126/scisignal.2004754)
[Settembre C et al., TFEB links autophagy to lysosomal biogenesis (2011) (2011)](https://doi.org/10.1126/science.1204592)
[Pastore N et al., TFE3 regulates whole-body energy metabolism in cooperation with TFEB (2017) (2017)](https://doi.org/10.15252/embr.201643204)
[Decressac M et al., TFEB-mediated autophagy rescues midbrain dopamine neurons from alpha-synuclein toxicity (2013) (2013)](https://doi.org/10.1073/pnas.1305623110)
[Sardiello M et al., A gene network regulating lysosomal biogenesis and function (2009) (2009)](https://doi.org/10.1126/science.1174447)
[Roczniak-Ferguson A et al., The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis (2012) (2012)](https://doi.org/10.1126/scisignal.2002790)
[Bordi M et al., Autophagy flux in CA1 neurons of Alzheimer hippocampus (2016) (2016)](https://doi.org/10.1080/15548627.2016.1185078)