Overexpression of 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 be mainly responsible for neurodegenerative diseases recently. Its involvement in nuclear factor-kappaB pathways has been reported in neuron and microglial cells that are linked to amyotrophic lateral sclerosis (ALS). Nuclear factor-kappaB (NF-κB) is a family that consists of five members that exist and function as dimers. NF-κB pathway targets more than hundreds of genes that are involved in inflammation, immunity and cancer. It also has functions in the nervous system. 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 are through the classic nuclear transportation system. In this study, we report that TDP-43 overexpression could block TNF-α induced p65 nuclear translocation dose dependently that further inhibits p65 transactivation activity. Furthermore, the inhibition by TDP-43 is not through preventing IκB degradation but probably by competing the nuclear transporter-importin α3 (KPNA4) and this competition is dependent on the presence of NLS in TDP-43. Silencing TDP-43 by a specific siRNA also increased p65 nuclear localization upon TNF-α stimulation, suggesting that endogenous TDP-43 may be a default suppressor of NF-κB pathway. The above results indicate that TDP-43 may play an important role in regulating the levels of NF-κB activity by control the nuclear translocation of p65.Surgery, Department ofMedicine, Faculty ofGraduat