Transcription Factor NF-κB Is Transported to the Nucleus via Cytoplasmic Dynein/Dynactin Motor Complex in Hippocampal Neurons

Mikenberg, Ilja; Widera, Darius; Kaus, Aljoscha; Kaltschmidt, Barbara; Kaltschmidt, Christian

doi:10.1371/journal.pone.0000589

Cited by 95 publications

(79 citation statements)

References 64 publications

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“…The continuous drive for the activation of NF-kB was suggested to be imparted by either post-synaptic activation mediated through the neurotransmitter glutamate or spontaneous calcium fluctuations (Kaltschmidt et al, 1995;Lilienbaum and Israël, 2003). This is mediated via post-synaptic activation and retrograde transport of p65/NF-kB from dendrites to the nucleus, using dynein-mediated transport mechanisms (Meffert et al, 2003;Mikenberg et al, 2007). We here demonstrate the potential existence of a second source of constitutive NF-kB activity in neurons that is controlled by FHF1 and requires NEMO, in line with the presumed essential role of NEMO in activation of the IKK-complex by a range of established stimuli (Yamaoka et al, 1998;Solt et al, 2009;Fenner et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor homologous factor 1 interacts with NEMO to regulate NF-κB signaling in neurons

König

Fenner

Byrne

et al. 2012

Journal of Cell Science

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SummaryNeuronal survival and plasticity critically depend on constitutive activity of the transcription factor nuclear factor-kB (NF-kB). We here describe a role for a small intracellular fibroblast growth factor homologue, the fibroblast growth factor homologous factor 1 (FHF1/ FGF12), in the regulation of NF-kB activity in mature neurons. FHFs have previously been described to control neuronal excitability, and mutations in FHF isoforms give rise to a form of progressive spinocerebellar ataxia. Using a protein-array approach, we identified FHF1b as a novel interactor of the canonical NF-kB modulator IKKc/NEMO. Co-immunoprecipitation, pull-down and GAL4-reporter experiments, as well as proximity ligation assays, confirmed the interaction of FHF1 and NEMO and demonstrated that a major site of interaction occurred within the axon initial segment. Fhf1 gene silencing strongly activated neuronal NF-kB activity and increased neurite lengths, branching patterns and spine counts in mature cortical neurons. The effects of FHF1 on neuronal NF-kB activity and morphology required the presence of NEMO. Our results imply that FHF1 negatively regulates the constitutive NF-kB activity in neurons.

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Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor homologous factor 1 interacts with NEMO to regulate NF-κB signaling in neurons

König

Fenner

Byrne

et al. 2012

Journal of Cell Science

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“…In neurons, spontaneous calcium transients maintain active NF-B in the nucleus (Kaltschmidt et al, 1994;Lilienbaum and Israël, 2003), presumably mediated by constitutively active phosphorylated IB-␣ and IKK in axon initial segment (Schultz et al, 2006) and at nodes of Ranvier (Politi et al, 2008). Depolarization or stimulation with glutamate leads to a redistribution of NF-B from neurites to the nucleus (Mikenberg et al, 2007) so that NF-B acts as a signal transducer, transmitting transient glutamatergic signals from distant synaptic sites to the nucleus (Kaltschmidt et al, 1994). In sensory neurons, constitutively active IKK regulates the activation threshold of TRP channels and dampens responses to acute nociceptive stimulation (Bockhart et al, 2009).…”

Section: F Proinflammatory Mediatorsmentioning

confidence: 99%

SNO-ing at the Nociceptive Synapse?

et al. 2011

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“…Studies examining the role of microtubules are conflicting, possibly because the pharmacological agents that disrupt microtubules result in a confounding activation of NF-B (4-10). Microtubule-dependent transport can also be probed by disrupting the multisubunit dynactin complex, and it was recently reported that dynactin could play a role in the nuclear accumulation of neuronal NF-B (10). Dynactin regulates the processivity of molecular motors using microtubules, including cytoplasmic dynein and kinesin (11,12).…”

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confidence: 99%

Stimulated nuclear translocation of NF-κB and shuttling differentially depend on dynein and the dynactin complex

Shrum¹,

DeFrancisco

Meffert

2009

Proc. Natl. Acad. Sci. U.S.A.

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Translocation from the cytoplasm to the nucleus is required for the regulation of gene expression by transcription factors of the nuclear factor kappa B (NF-B) family. The p65:p50 NF-B heterodimer that predominates in many cell types can undergo stimulated movement, following degradation of the I B inhibitor, as well as shuttling in the absence of stimulation with I B bound. Disruption of the dynactin complex and knockdown of endogenous dynein were used to investigate the nuclear translocation requirements for stimulated and shuttling movement of NF-B. A differential dependence of these two modes of transport on the dynein molecular motor and dynactin was found. NF-B used active dynein-dependent transport following stimulation while translocation during shuttling was mediated by a dynein-independent pathway that could be potentiated by dynactin disruption, consistent with a process of facilitated diffusion. Nuclear translocation and activation of NF-B-dependent gene expression showed a dependence on endogenous dynein in a variety of cell types and in response to diverse activating stimuli, suggesting that dyneindependent transport of NF-B may be a conserved mechanism in the NF-B activation pathway and could represent a potential point of regulation.NF-kappaB ͉ nuclear transport ͉ transcription ͉ molecular motor ͉ active transport T he NF-B or Rel transcription factors are ubiquitouslyexpressed regulators of gene expression that are essential for physiological processes ranging from innate and adaptive immunity to learning and memory. NF-B functions as a dimer and is retained in a latent form in the cytoplasm, bound to the inhibitor of NF-B (I B). In the canonical pathway, incoming stimuli trigger activation of the I B-kinase complex (IKK) that phosphorylates I B␣ and leads to its degradation. The subsequent translocation of active I B-free NF-B from cytoplasm to nucleus is critical for NF-B-dependent gene expression. In the absence of I B degradation, NF-B can undergo stimulusindependent movement back and forth between the nucleus and cytoplasm in a process termed shuttling (1). Shuttling of p65:p50 NF-B dimers is believed to result from incomplete masking of the p50 nuclear localization sequence (NLS) by bound I B␣ and can be observed by blocking exportin1/crm1-mediated nuclear export under unstimulated conditions (2).While NF-B requires importin family members to cross the nuclear pore (3), the molecular mechanisms underlying NF-B cytoplasmic movement remain poorly understood. Studies examining the role of microtubules are conflicting, possibly because the pharmacological agents that disrupt microtubules result in a confounding activation of NF-B (4-10). Microtubule-dependent transport can also be probed by disrupting the multisubunit dynactin complex, and it was recently reported that dynactin could play a role in the nuclear accumulation of neuronal NF-B (10). Dynactin regulates the processivity of molecular motors using microtubules, including cytoplasmic dynein and kinesin (11,12). Dynein is a retrograde m...

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Transcription Factor NF-κB Is Transported to the Nucleus via Cytoplasmic Dynein/Dynactin Motor Complex in Hippocampal Neurons

Cited by 95 publications

References 64 publications

Fibroblast growth factor homologous factor 1 interacts with NEMO to regulate NF-κB signaling in neurons

Fibroblast growth factor homologous factor 1 interacts with NEMO to regulate NF-κB signaling in neurons

SNO-ing at the Nociceptive Synapse?

Stimulated nuclear translocation of NF-κB and shuttling differentially depend on dynein and the dynactin complex

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