CRL4 targets Elongin C for ubiquitination and degradation to modulate CRL5 signaling.

Multi-subunit cullin-RING ligases (CRLs) are the largest family of ubiquitin E3 ligases in humans. CRL activity is tightly regulated to prevent unintended substrate degradation or autocatalytic degradation of CRL subunits. Using a proteomics strategy, we discovered that CRL4(AMBRA1) (CRL substrate receptor denoted in superscript) targets Elongin C (ELOC), the essential adapter protein of CRL5 complexes, for polyubiquitination and degradation. We showed that the ubiquitin ligase function of CRL4(AMBRA1) is required to disrupt the assembly and attenuate the ligase activity of human CRL5(SOCS3) and HIV-1 CRL5(VIF) complexes as AMBRA1 depletion leads to hyperactivation of both CRL5 complexes. Moreover, CRL4(AMBRA1) modulates interleukin-6/STAT3 signaling and HIV-1 infectivity that are regulated by CRL5(SOCS3) and CRL5(VIF), respectively. Thus, by discovering a substrate of CRL4(AMBRA1), ELOC, the shared adapter of CRL5 ubiquitin ligases, we uncovered a novel CRL cross-regulation pathway.