title: RNA-processing protein TDP-43 regulates FOXO-dependent protein quality control in stress response.
abstract: Protein homeostasis is critical for cell survival and functions during stress and is regulated at both RNA and protein levels. However, how the cell integrates RNA-processing programs with post-translational protein quality control systems is unknown. Transactive response DNA-binding protein (TARDBP/TDP-43) is an RNA-processing protein that is involved in the pathogenesis of major neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we report a conserved role for TDP-43, from C. elegans to mammals, in the regulation of protein clearance via activation of FOXO transcription factors. In response to proteotoxic insults, TDP-43 redistributes from the nucleus to the cytoplasm, promoting nuclear translocation of FOXOs and relieving an inhibition of FOXO activity in the nucleus. The interaction between TDP-43 and the FOXO pathway in mammalian cells is mediated by their competitive binding to 14-3-3 proteins. Consistent with FOXO-dependent protein quality control, TDP-43 regulates the levels of misfolded proteins. Therefore, TDP-43 mediates stress responses and couples the regulation of RNA metabolism and protein quality control in a FOXO-dependent manner. The results suggest that compromising the function of TDP-43 in regulating protein homeostasis may contribute to the pathogenesis of related neurodegenerative diseases.
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland, United States of America, 2 Department of Neuroscience, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland, United States of America, 2 Department of Neuroscience, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Gerard
authors.initials: G
authors.lastname: Baldie
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland, United States of America, 2 Department of Neuroscience, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Goran
authors.initials: G
authors.lastname: Periz
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland, United States of America, 2 Department of Neuroscience, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Jiou
authors.initials: J
authors.lastname: Wang
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008136:Longevity; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D048948:14-3-3 Proteins; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D016601:RNA-Binding Proteins; C000598624:TARDBP protein, human; C000595270:TDP-1 protein, C elegans; C108831:daf-16 protein, C elegans