Abstract
The kinase PINK1 and ubiquitin ligase Parkin can regulate the selective elimination of damaged mitochondria through autophagy (mitophagy). Because of the demand on lysosomal function by mitophagy, we investigated a role for the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, in this process. We show that during mitophagy TFEB translocates to the nucleus and displays transcriptional activity in a PINK1- and Parkin-dependent manner. MITF and TFE3, homologues of TFEB belonging to the same microphthalmia/transcription factor E (MiT/TFE) family, are similarly regulated during mitophagy. Unlike TFEB translocation after starvation-induced mammalian target of rapamycin complex 1 inhibition, Parkin-mediated TFEB relocalization required Atg9A and Atg5 activity. However, constitutively active Rag guanosine triphosphatases prevented TFEB translocation during mitophagy, suggesting cross talk between these two MiT/TFE activation pathways. Analysis of clustered regularly interspaced short palindromic repeats-generated TFEB/MITF/TFE3/TFEC single, double, and triple knockout cell lines revealed that these proteins partly facilitate Parkin-mediated mitochondrial clearance. These results illuminate a pathway leading to MiT/TFE transcription factor activation, distinct from starvation-induced autophagy, which occurs during mitophagy.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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14-3-3 Proteins / metabolism
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Active Transport, Cell Nucleus
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Autophagy / genetics
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Autophagy / physiology*
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Autophagy-Related Protein 5
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Autophagy-Related Proteins
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
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Cell Line, Tumor
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Gene Knockout Techniques
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HEK293 Cells
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HeLa Cells
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Homeodomain Proteins / metabolism
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Humans
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Lysosomes / metabolism
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Mechanistic Target of Rapamycin Complex 1
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Microphthalmia-Associated Transcription Factor / genetics
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism*
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Mitochondria / metabolism
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Mitochondrial Proteins / genetics
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Mitophagy / genetics
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Mitophagy / physiology*
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Multiprotein Complexes / antagonists & inhibitors
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Phagosomes / metabolism
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Protein Kinases / genetics
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RNA Interference
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RNA, Small Interfering
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Vesicular Transport Proteins / metabolism
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rab GTP-Binding Proteins / genetics
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rab7 GTP-Binding Proteins
Substances
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14-3-3 Proteins
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ATG5 protein, human
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ATG9A protein, human
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Autophagy-Related Protein 5
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Autophagy-Related Proteins
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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FIS1 protein, human
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Homeodomain Proteins
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MITF protein, human
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Membrane Proteins
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Microphthalmia-Associated Transcription Factor
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Microtubule-Associated Proteins
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Mitochondrial Proteins
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Multiprotein Complexes
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RNA, Small Interfering
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TFE3 protein, human
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TFEB protein, human
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Vesicular Transport Proteins
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rab7 GTP-Binding Proteins
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RAG-1 protein
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Ubiquitin-Protein Ligases
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parkin protein
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Protein Kinases
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Mechanistic Target of Rapamycin Complex 1
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PTEN-induced putative kinase
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TOR Serine-Threonine Kinases
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rab GTP-Binding Proteins