Cullin-RING ubiquitin ligases: global regulation and activation cycles

Abstract

Cullin-RING ubiquitin ligases (CRLs) comprise the largest known category of ubiquitin ligases. CRLs regulate an extensive number of dynamic cellular processes, including multiple aspects of the cell cycle, transcription, signal transduction, and development. CRLs are multisubunit complexes composed of a cullin, RING H2 finger protein, a variable substrate-recognition subunit (SRS), and for most CRLs, an adaptor that links the SRS to the complex. Eukaryotic species contain multiple cullins, with five major types in metazoa. Each cullin forms a distinct class of CRL complex, with distinct adaptors and/or substrate-recognition subunits. Despite this diversity, each of the classes of CRL complexes is subject to similar regulatory mechanisms. This review focuses on the global regulation of CRL complexes, encompassing: neddylation, deneddylation by the COP9 Signalosome (CSN), inhibitory binding by CAND1, and the dimerization of CRL complexes. We also address the role of cycles of activation and inactivation in regulating CRL activity and switching between substrate-recognition subunits.

Set them free: F-box protein exchange by Cand1

“…Nedd8 deconjugation is catalyzed by the COP9 signalosome (CSN). Strikingly, the paradox observed for Cand1 is also evident for CSN, because CSN clearly functions as a negative regulator of SCF in vitro, yet genetic data suggest a positive role for SCF activity in vivo [5]. A prevailing model has been that SCF and other CRLs must undergo neddylation cycles whereby deneddylated cullins are sequestered by Cand1, allowing substrate receptor exchange followed by reactivation of the assembled CRL by neddylation.…”

“…However, its true function was somewhat of a mystery. Cand1 acted as a potent SCF inhibitor in vitro by displacing the FboxP-Skp1 pair from Cul1, but genetic experiments classified Cand1 as a positive regulator of SCF and other CRLs in vivo [5]. An additional layer of complexity is added by covalent modification of cullins with the ubiquitin-like protein Nedd8.…”

PEST sequences mediate heat shock factor 2 turnover by interacting with the Cul3 subunit of the Cul3-RING ubiquitin ligase

“…It has previously been shown that this can be mediated by interaction between substrate proteins and BTB domain-containing subunits of the ubiquitin ligase complexes (Bosu and Kipreos 2008;Hotton and Callis 2008;Petroski and Deshaies 2005;Sumara et al 2008). However, our results indicate that recruitment can also occur by interaction between PEST sequences in a substrate protein, in this case HSF2, and the Cul3 subunit of the Cul3-RING ligase complexes.…”

“…Cul3, a member of the Cullin family of proteins, is a subunit of a Cullin-RING ubiquitin E3 ligase complex that polyubiquitinates many important proteins, leading to their degradation by the proteasome (Bosu and Kipreos 2008;Hotton and Callis 2008;Petroski and Deshaies 2005;Sumara et al 2008). Cul3-containing ubiquitin ligases have been found to play important roles in the regulation of mitosis, development, cytoskeletal proteins, and transcription factors (Pintard et al 2004;Sumara et al 2008;.…”

SYVN1, NEDD8, and FBXO2 Proteins Regulate ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitin-mediated Proteasomal Degradation

“…NEDD8 is a ubiquitin-like protein that is covalently attached to its substrates. Cullins form the largest class of NEDD8 substrates, and attachment of NEDD8 to cullins activates their associated E3 ubiquitin ligase activity and thus promotes polyubiquitination and proteasomal degradation of target proteins (28). The identification of these two genes whose functions converge on the polyubiquitination and proteasomal degradation pathway led us to hypothesize that SYVN1 and NEDD8 promote ⌬F508-CFTR polyubiquitination and that depleting either protein would improve ⌬F508-CFTR maturation in CF cells.…”