NF-κB regulates neuronal ankyrin-G via a negative feedback loop.
The axon initial segment (AIS) is a neuronal compartment defined by ankyrin-G expression. We here demonstrate that the IKK-complex co-localizes and interacts with the cytoskeletal anchor protein ankyrin-G in immunoprecipitation and proximity-ligation experiments in cortical neurons. Overexpression of the 270 kDa variant of ankyrin-G suppressed, while gene-silencing of ankyrin-G expression increased nuclear factor-κB (NF-κB) activity in primary neurons, suggesting that ankyrin-G sequesters the transcription factor in the AIS. We also found that p65 bound to the ank3 (ankyrin-G) promoter sequence in chromatin immunoprecipitation analyses thereby increasing ank3 expression and ankyrin-G levels at the AIS. Gene-silencing of p65 or ankyrin-G overexpression suppressed ank3 reporter activity. Collectively these data demonstrate that p65/NF-κB controls ankyrin-G levels via a negative feedback loop, thereby linking NF-κB signaling with neuronal polarity and axonal plasticity.
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland.|Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland.
Hans-Georg
HG
König
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland.|Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland.
Robert
R
Schwamborn
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland.
Silke
S
Andresen
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland.|Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland.
Sinéad
S
Kinsella
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland.|Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland.
Orla
O
Watters
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland.
Beau
B
Fenner
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland.|Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland.
Jochen H M
JH
Prehn
D000818:Animals; D017487:Ankyrins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D025461:Feedback, Physiological; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D019579:Neocortex / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051381:Rats; D051996:Transcription Factor RelA / Q000378:metabolism*
D017487:Ankyrins; D051996:Transcription Factor RelA