Abstract
BackgroundLong-term changes in synaptic plasticity require gene transcription, indicating that signals generated at the synapse must be transported to the nucleus. Synaptic activation of hippocampal neurons is known to trigger retrograde transport of transcription factor NF-κB. Transcription factors of the NF-κB family are widely expressed in the nervous system and regulate expression of several genes involved in neuroplasticity, cell survival, learning and memory.Principal FindingsIn this study, we examine the role of the dynein/dynactin motor complex in the cellular mechanism targeting and transporting activated NF-κB to the nucleus in response to synaptic stimulation. We demonstrate that overexpression of dynamitin, which is known to dissociate dynein from microtubules, and treatment with microtubule-disrupting drugs inhibits nuclear accumulation of NF-κB p65 and reduces NF-κB-dependent transcription activity. In this line, we show that p65 is associated with components of the dynein/dynactin complex in vivo and in vitro and that the nuclear localization sequence (NLS) within NF-κB p65 is essential for this binding.ConclusionThis study shows the molecular mechanism for the retrograde transport of activated NF-κB from distant synaptic sites towards the nucleus.
Highlights
Rel/NF-kB proteins are a family of transcription factors involved in regulating the expression of genes relevant in a wide range of different cellular processes, such as apoptosis and cell survival, stress and immune response, differentiation and proliferation [1], [2]
We provide evidence suggesting the requirement of dynein/dynactin motor complex in retrograde transport of NF-kB following synaptic activation of hippocampal neurons
NF-kB p65 was found to coprecipitate with the intermediate chain of cytoplasmic dynein (IC74) and with two members of the dynactin family: dynactin p50 (Dynamitin) and p150Glued
Summary
Rel/NF-kB proteins are a family of transcription factors involved in regulating the expression of genes relevant in a wide range of different cellular processes, such as apoptosis and cell survival, stress and immune response, differentiation and proliferation [1], [2]. We examine the role of the dynein/dynactin motor complex in the cellular mechanism targeting and transporting activated NF-kB to the nucleus in response to synaptic stimulation. We demonstrate that overexpression of dynamitin, which is known to dissociate dynein from microtubules, and treatment with microtubule-disrupting drugs inhibits nuclear accumulation of NF-kB p65 and reduces NF-kB-dependent transcription activity. In this line, we show that p65 is associated with components of the dynein/dynactin complex in vivo and in vitro and that the nuclear localization sequence (NLS) within NF-kB p65 is essential for this binding. This study shows the molecular mechanism for the retrograde transport of activated NF-kB from distant synaptic sites towards the nucleus
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