TDP-43 Inhibits NF-κB Activity by Blocking p65 Nuclear Translocation

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-kappa B 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-kappa B 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-alpha 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 I kappa B degradation but probably by competing for the nuclear transporter-importin alpha 3 (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-alpha stimulation, suggesting that endogenous TDP-43 may be a default suppressor of the NF-kappa B pathway. Our results indicate that TDP-43 may play an important role in regulating the levels of NF-kappa B activity by controlling the nuclear translocation of p65.