Activating molecule in BECN1-regulated autophagy protein 1
ubiquitin-like ligase-substrate adaptor activity
CRL4<sup>AMBRA1</sup> 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<sup>AMBRA</sup><sup>1</sup> (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<sup>AMBRA</sup><sup>1</sup> is required to disrupt the assembly and attenuate the ligase activity of human CRL5<sup>SOCS</sup><sup>3</sup> and HIV-1 CRL5<sup>VIF</sup> complexes as AMBRA1 depletion leads to hyperactivation of both CRL5 complexes. Moreover, CRL4<sup>AMBRA</sup><sup>1</sup> modulates interleukin-6/STAT3 signaling and HIV-1 infectivity that are regulated by CRL5<sup>SOCS</sup><sup>3</sup> and CRL5<sup>VIF</sup>, respectively. Thus, by discovering a substrate of CRL4<sup>AMBRA</sup><sup>1</sup>, ELOC, the shared adapter of CRL5 ubiquitin ligases, we uncovered a novel CRL cross-regulation pathway.