Proteasome-dependent and -independent mechanisms for FosB destabilization:: identification of FosB degron domains and implications for ΔFosB stability

The transcription factor Delta FosB (Delta FosB) accumulates in a region-specific manner in the brain during chronic exposure to stress, drugs of abuse or other chronic stimuli. Once induced, Delta FosB persists in the brain for at least several weeks following cessation of the chronic stimulus. The biochemical basis of the persistent expression of Delta FosB has remained unknown. Here, we show that the FosB C-terminus, absent in Delta FosB as a result of alternative splicing, contains two degron domains. Pulse-chase experiments of C-terminal truncation mutants of full-length FosB indicate that removal of its most C-terminal degron increases its half-life similar to fourfold, and prevents its proteasome-mediated degradation and ubiquitylation, properties similar to Delta FosB. In addition, removal of a second degron domain, which generates Delta FosB, further stabilizes FosB similar to twofold, but in a proteasome-independent manner. These data indicate that alternative splicing specifically removes two destabilizing elements from FosB in order to generate a longer-lived transcription factor, Delta FosB, in response to chronic perturbations to the brain.