Abstract
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 CRL4AMBRA1 (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 CRL4AMBRA1 is required to disrupt the assembly and attenuate the ligase activity of human CRL5SOCS3 and HIV‐1 CRL5VIF complexes as AMBRA1 depletion leads to hyperactivation of both CRL5 complexes. Moreover, CRL4AMBRA1 modulates interleukin‐6/STAT3 signaling and HIV‐1 infectivity that are regulated by CRL5SOCS3 and CRL5VIF, respectively. Thus, by discovering a substrate of CRL4AMBRA1, ELOC, the shared adapter of CRL5 ubiquitin ligases, we uncovered a novel CRL cross‐regulation pathway.
Synopsis

The ubiquitin E3 ligase CRL4AMBRA1 targets Elongin C (ELOC), the shared adapter of CRL5 ubiquitin ligases, for polyubiquitination and degradation, thereby modulating IL‐6/STAT3 signaling and HIV‐1 infectivity that are regulated by CRL5SOCS3 and HIV‐1 CRL5VIF, respectively.
Quantitative proteomics identifies ELOC as a novel substrate of CRL4AMBRA1.
ELOC mediates the interaction between AMBRA1 and multiple CRL5 substrate receptors.
ELOC targeting by CRL4AMBRA1 attenuates the ligase activity of CRL5SOCS3 and HIV‐1 CRL5VIF.
CRL4AMBRA1 modulates CRL5SOCS3‐ and HIV‐1 CRL5VIF‐regulated functions.
The EMBO Journal (2018) 37: e97508
- Received June 5, 2017.
- Revision received July 26, 2018.
- Accepted August 1, 2018.
- © 2018 The Authors
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