Ubiquitin-independent- versus ubiquitin-dependent proteasomal degradation of the c-Fos and Fra-1 transcription factors: is there a unique answer?

The Fos family of transcription factors comprises c-Fos, Fra-1, Fra-2 and FosB, which are all intrinsically unstable proteins. Fos proteins heterodimerize with a variety of other transcription factors to control genes encoding key cell regulators. Their best known partners are the Jun family proteins (c-Jun, JunB, and JunD). At the cellular level, Fos-involving dimers control proliferation, differentiation, apoptosis and responses to environmental cues. At the organism level, they play paramount parts in organogenesis, immune responses and cognitive functions, among others. fos family genes are subjected to exquisite, complex and intermingled transcriptional and post-transcriptional regulations, which are necessary to avoid pathological effects. In particular, the Fos proteins undergo to numerous post-translational modifications, such as phosphorylations and sumoylation, regulating their transcriptional activity, their subcellular localization and their turnover. The mechanisms whereby c-Fos and Fra-1 are degraded have been studied in detail. Contrasting with the classical scenario, according to which most unstable key cell regulators are hydrolyzed by the proteasome after conjugation of polyubiquitin chains, the bulk of c-Fos and Fra-1 can be hydrolyzed independently of any prior ubiquitylation in different situations. c-Fos and Fra-1 share a common destabilizing domain whose primary sequence is conserved in Fra-2 and FosB, suggesting that similar breakdown mechanisms might be at play in the latter two proteins. However, a database search indicates that this domain is not found in any other protein, suggesting that the mechanisms underlying Fos protein destruction may be specific to this family. Interestingly, under particular conditions, a fraction of cytoplasmic c-Fos is ubiquitylated, leading to faster turnover. This poses the question of the multiplicity of degradation pathways that can target the same substrate depending on its activation state, its protein partnership and/or its intracellular localization. This issue is discussed here together with the, thus far, overlooked roles of the various proteasomal complexes found in all cells.