RNA-Processing Protein TDP-43 Regulates FOXO-Dependent Protein Quality Control in Stress Response

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TDP-43 is linked to pathogenesis of major neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How TDP-43 contributes to the development of these degenerative diseases remains unsolved, and the full range of TDP-43 functions has yet to be established. In the present study, we explored a conversed function of TDP-43 in regulating protein homeostasis from C. elegans to mammals. Under conditions of stress, TDP-43 translocates from the nucleus to the cytoplasm, competes with FOXO transcription factors for binding to 14-3-3 proteins, and releases FOXO for nuclear translocation and activation. These data are consistent with the ability of TDP-43 to regulate protein aggregation. Together the results provide important insight into the role of TDP-43 in stress responses and disease mechanisms. Since chronic stress is associated with neurodegenerative diseases, the TDP-43 switch could be kept in overdrive mode in these disorders, with its capacity to buffer further stress and maintain protein homeostasis being compromised. This mechanism also suggests that other RNA-processing proteins that exhibit similar stress-induced behavior may be coupled to other cellular pathways to provide coordinated reprogramming in stress responses.

Vyšlo v časopise: RNA-Processing Protein TDP-43 Regulates FOXO-Dependent Protein Quality Control in Stress Response. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004693
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004693

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