Figure 6. Schematic model depicting the regulation of spastin protein levels.

Because S268-phosphorylation (indicated with a blue P) prevents polyubiquitination of spastin, its protein levels are the consequence of a balance between phosphorylation and degradation events depending on HIPK2 kinase activity and the function of a still unknown CRL complex. Based on this model, low HIPK2 activity reduces the spastin phosphorylated forms leading to an increase of spastin polyubiquitination with a consequent decrease of spastin protein levels due to proteasomal degradation. In contrast, high HIPK2 activity protects spastin from polyubiquitination, increasing its protein levels. When polyubiquitination is prevented using the neddylation inhibitor, MLN4924, spastin protein levels increase independently of its phosphorylation status.