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

• DOI: 10.1371/journal.pgen.1004693
• Publication Date: 2014-10-20T17:28:21Z
• Authors: Tao Zhang; Gerard Baldie; Goran Periz; Jiou Wang
• Keywords: 0301 basic medicine; Cytoplasm; Forkhead Box Protein O1; Forkhead Box Protein O3; Longevity; RNA-Binding Proteins; Forkhead Transcription Factors; QH426-470; 3. Good health; Animals, Genetically Modified; DNA-Binding Proteins; 03 medical and health sciences; HEK293 Cells; 14-3-3 Proteins; Stress, Physiological; Genetics; Animals; Humans; Female; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Research Article

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.