Sepe Maria, Lignitto Luca, Porpora Monia, Delle Donne Rossella, Rinaldi Laura, Belgianni Giuseppe, Colucci Gianna, Cuomo Ornella, Viggiano Davide, Scorziello Antonella, Garbi Corrado, Annunziato Lucio, Feliciello Antonio
Dipartimento di Medicina Molecolare e Biotecnologie Mediche and.
Dipartimento di Neuroscienze, Scienze Riproduttive ed Odontostomatologiche, University Federico II, 80131 Naples, Italy.
Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):15729-34. doi: 10.1073/pnas.1410274111. Epub 2014 Oct 20.
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.
蛋白激酶A（PKA）控制着神经突生长和形态发生的主要方面，并在突触可塑性和记忆中发挥着至关重要的作用。然而，PKA对神经突萌发和活性作用的分子机制仍然未知。在此，我们报告，响应神经营养因子或cAMP刺激，RING连接酶praja2使哺乳动物脑中神经突生长的主要抑制剂NOGO-A发生泛素化并降解。praja2的基因沉默严重抑制了分化中的神经母细胞瘤细胞和中脑神经元的神经突延伸，以及发育中大鼠脑内纹状体终末的轴突生长和萌发。当praja2和NOGO-A都被耗尽时，这种表型得以挽救，这表明NOGO-A确实是praja2在神经元细胞中的一个生物学相关靶点。我们的发现揭示了一种新机制，该机制将cAMP信号与NOGO-A的蛋白水解周转功能耦合，对哺乳动物脑中的神经突生长产生积极影响。
