Proteolytic control of neurite outgrowth inhibitor NOGO-A by the cAMP/PKA pathway

Maria Sepe, Luca Lignitto, Monia Porpora, Rossella Delle Donne, Laura Rinaldi, Giuseppe Belgianni, Gianna Colucci, Ornella Cuomo, Davide Viggiano, Antonella Scorziello, Corrado Garbi, Lucio Annunziato, Antonio Feliciello

Research output: Contribution to journalArticle

Abstract

Protein kinase A (PKA) controls major aspects of neurite outgrowth and morphogenesis and plays an essential role in synaptic plasticity and memory. However, the molecular mechanism(s) of PKA action on neurite sprouting and activity are still unknown. Here, we report that in response to neurotrophin or cAMP stimulation the RING ligase praja2 ubiquitinates and degrades NOGO-A, a major inhibitor of neurite outgrowth in mammalian brain. Genetic silencing of praja2 severely inhibited neurite extension of differentiating neuroblastoma cells and mesencephalic neurons and axon outgrowth and sprouting of striatal terminals in developing rat brain. This phenotype was rescued when both praja2 and NOGO-A were depleted, suggesting that NOGO-A is, indeed, a biologically relevant target of praja2 in neuronal cells. Our findings unveil a novel mechanism that functionally couples cAMP signaling with the proteolytic turnover of NOGO-A, positively impacting on neurite outgrowth in mammalian brain.

Original languageEnglish
Pages (from-to)15729-15734
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number44
DOIs
Publication statusPublished - Nov 4 2014

Keywords

  • CAMP
  • NOGO-A
  • PKA
  • Proteasome
  • Ubiquitin

ASJC Scopus subject areas

  • General
  • Medicine(all)

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    Sepe, M., Lignitto, L., Porpora, M., Donne, R. D., Rinaldi, L., Belgianni, G., Colucci, G., Cuomo, O., Viggiano, D., Scorziello, A., Garbi, C., Annunziato, L., & Feliciello, A. (2014). Proteolytic control of neurite outgrowth inhibitor NOGO-A by the cAMP/PKA pathway. Proceedings of the National Academy of Sciences of the United States of America, 111(44), 15729-15734. https://doi.org/10.1073/pnas.1410274111