The ubiquitin–proteasome system at the crossroads of stress-response and ageing pathways: A handle for skin care?

The regulation of gene expression at the transcriptional level has been considered for long as the main mechanism of cellular adaptive responses. Since the turn of the century, however, it is becoming clear that higher organisms developed a complex, sensitive and maybe equally important network of regulatory pathways, relying largely on protein interactions, post-translational modifications and proteolysis. Here we review the involvement of the ubiquitin–proteasome pathway of protein degradation at different levels of cellular life in relation with ageing, and with a special focus on skin. It comes out that the ubiquitin system plays a major role in signal transduction associated with stress and ageing, in skin in particular through the control of retinoid and NF-κB pathways. The understanding of specific proteolytic targeting by E3 ubiquitin-ligases paves the way for a new generation of active molecules that may control particular steps of normal and pathological ageing.