Control of IκBα proteolysis by the ubiquitin-proteasome pathway

It has recently been determined that the proteolytic destruction of I kappaB (inhibitor of NF-kappaB) by the ubiquitin-proteasome system plays a key role in the immediate elimination of I kappaB from the I kappaB-(NF-kappaB) complex which allows nuclear translocation of free NF-KB, thus leading to activation of a multitude of target genes. The SCFFbw1 (composed of Skp1, Cul-1, Rod, and Fbw1) complex, identified as an I kappaB alpha -E3 ligase, binds and ubiquitylates I kappaB alpha phosphorylated by I kappaB kinase that has been activated in response to extracellular signals. The generating poly-ubiquitin chain is finally recognized by the 26S proteasome for ultimate degradation. In this NF-kappaB signalling pathway, it becomes clear that the SCFFbw1 activity is enhanced by a ubiquitin-like protein NEDD8 (equivalent to Rub1) that modifies Cul-1 in a manner analogous to ubiquitylation, and consequently, I kappaB alpha proteolysis is induced. NEDD8 is a new regulator of the SCF ubiquitin-ligase, functioning as a covalent modifier for proteolytic targeting at a physiological level. (C) 2001 Societe francaise de biochimie et biologie moleculaire / Editions scientifiques et medicales Elsevier SAS. All rights reserved.