title: TDP-43 Inhibits NF-κB Activity by Blocking p65 Nuclear Translocation.
abstract: TDP-43 (TAR DNA binding protein 43) is a heterogeneous nuclear ribonucleoprotein (hnRNP) that has been found to play an important role in neurodegenerative diseases. TDP-43's involvement in nuclear factor-kappaB pathways has been reported in both neurons and microglial cells. The NF-κB pathway targets hundreds of genes, many of which are involved in inflammation, immunity and cancer. p50/p65 (p50/RelA) heterodimers, as the major Rel complex in the NF-κB family, are induced by diverse external physiological stimuli and modulate transcriptional activity in almost all cell types. Both p65 and TDP-43 translocation occur through the classic nuclear transportation system. In this study, we report that TDP-43 overexpression prevents TNF-α induced p65 nuclear translocation in a dose dependent manner, and that this further inhibits p65 transactivation activity. The inhibition by TDP-43 does not occur through preventing IκB degradation but probably by competing for the nuclear transporter-importin α3 (KPNA4). This competition is dependent on the presence of the nuclear localization signal (NLS) in TDP-43. Silencing TDP-43 using a specific siRNA also increased p65 nuclear localization upon TNF-α stimulation, suggesting that endogenous TDP-43 may be a default suppressor of the NF-κB pathway. Our results indicate that TDP-43 may play an important role in regulating the levels of NF-κB activity by controlling the nuclear translocation of p65.
authors.affiliation: Brain Research Center, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T2B5, Canada.|Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jingyan
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Brain Research Center, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T2B5, Canada.
authors.forename: Max S
authors.initials: MS
authors.lastname: Cynader
authors.affiliation: Brain Research Center, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T2B5, Canada.|Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Jia
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001667:Binding, Competitive; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D061986:MCF-7 Cells; D019913:Nuclear Localization Signals / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D051996:Transcription Factor RelA / Q000378:metabolism*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D028901:alpha Karyopherins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; C106259:KPNA4 protein, human; D019913:Nuclear Localization Signals; D029543:Nucleocytoplasmic Transport Proteins; C498143:RELA protein, human; C000598624:TARDBP protein, human; C439524:TNF protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D028901:alpha Karyopherins