UCSF

Multi-subunit Cullin-RING ligases (CRLs) comprise the largest family of ubiquitin E3 ligases in humans. Although some CRLs attenuates substrate degradation, it remains unclear whether their modularity can be targeted to regulate CRL subfamilies. With proteomics, we discovered cross talk between CRL4AMBRA1 and CRL5VIF. We also found that CRL4AMBRA1 targets Elongin C (ELOC), the essential adapter protein of CRL5 and CRL2 complexes, for polyubiquitination and proteasomal degradation. Depletion of AMBRA1 promotes accumulation of ELOC, which enhances ligase activity and autocatalysis of CRL5 and CRL2 substrate receptors. We also found that CRL4AMBRA1 reduces the assembly and ligase activity of both CRL5SOCS3 and HIV-1 CRL5VIF complexes. Furthermore, AMBRA1 depletion blunts IL-6-induced STAT3 phosphorylation and enhances the degradation of the antiviral APOBEC3G protein, which are regulated by CRL5SOCS3 and CRL5VIF, respectively. Thus, we revealed that CRL4AMBRA1 negatively regulates CRL5 ubiquitin E3 ligases by targeting their shared ELOC for degradation.