CRL5

CRL5, or Cullin-RING ligase 5, is a member of the Cullin-RING ligase (CRL) family of E3 ubiquitin ligases. It uses Cul5 as a scaffold to assemble a multi-subunit complex that tags specific substrate proteins with ubiquitin, marking them for degradation by the 26S proteasome. The core CRL5 complex comprises Cul5, the RING finger protein Rbx2 (RBX2), and the adaptor proteins Elongin B and Elongin C. Substrate recognition is conferred by a repertoire of SOCS box-containing substrate receptors, including SOCS family members (SOCS1–SOCS7 and related proteins) and other SOCS-like receptors.

Substrate selection by CRL5 is highly context-dependent, enabling the degradation of diverse targets such as components of cytokine signaling pathways, transcription factors, and other regulatory proteins. A common mode is through SOCS proteins that bind phospho-tyrosine–containing signaling complexes and concurrently recruit Cul5 via the SOCS box, promoting ubiquitination of the bound target(s).

Biological roles of CRL5 include negative regulation of cytokine and growth factor signaling, immune response modulation, and development. Aberrations in CRL5 components or their substrates have been linked to diseases including cancer and developmental disorders, reflecting the importance of controlled protein turnover. The activity of CRL5 is regulated by the neddylation/deneddylation cycle, with Nedd8 modification of Cul5 required for efficient ubiquitin transfer, and by cellular signals that alter substrate receptor expression.

Research on CRL5 continues to map substrate networks and their physiological contexts, and the CRL5 axis is considered a potential target for therapeutic intervention in diseases driven by dysregulated protein degradation.