Cullin RING Ligase 5 (CRL-5): Neddylation Activation and Biological Functions

Cullin-5 (Cul-5) was originally identified as an arginine vasopressin (AVP) receptor due to its homology to a vasopressin-activated calcium-mobilizing protein 1 (VACM-1). Cul-5 has subsequently gained much attention after being identified as the key component of CRL-5 (Cullin-RING ligase-5) that mediates ubiquitylation and degradation of several key cellular proteins associated with human cancers and viral infections. Structurally, Cul-5 interacts with the Elongin B/C complex, a RING finger protein (RBX2/SAG), and a SOCS protein to form a CRL-5 E3 ubiquitin ligase protein complex. CRL-5, by controlling turnover of a variety of substrates, is implicated in several biological processes and human diseases. Activation of CRL-5 requires Cul-5 neddylation, catalyzed by a neddylation enzyme cascade, consisting of the E1 NEDD8-activating enzyme (NAE), the E2 neddylation conjugating enzyme (UBE2F), and E3 neddylation ligase (RBX2/SAG). RBX2/SAG, therefore, serves as both Cul-5 neddylation E3 and CRL-5 ubiquitylation E3. Here, we review the current knowledge on CRL-5, its activation by the UBE2F-SAG, its regulation of various signaling pathways via substrate degradation, and its implications in human cancers.