| Summary: | 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.
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