title: MiT/TFE transcription factors are activated during mitophagy downstream of Parkin and Atg5.
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.
authors.affiliation: Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Nezich
authors.affiliation: Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Chunxin
authors.initials: C
authors.lastname: Wang
authors.affiliation: Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Adam I
authors.initials: AI
authors.lastname: Fogel
authors.affiliation: Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 youler@ninds.nih.gov.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics; D063306:Mitophagy / Q000235:genetics / Q000502:physiology*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D010588:Phagosomes / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics; D000090802:rab7 GTP-Binding Proteins; D000099202:PTEN-Induced Putative Kinase
chemical_list: D048948:14-3-3 Proteins; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018398:Homeodomain Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins; D051739:Microphthalmia-Associated Transcription Factor; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D011494:Protein Kinases; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins; D000099202:PTEN-Induced Putative Kinase; C502778:ATG5 protein, human; C574794:ATG9A protein, human; C476525:FIS1 protein, human; C497234:MITF protein, human; C069203:TFE3 protein, human; C064972:TFEB protein, human; C064658:RAG-1 protein; C111567:parkin protein