CRL4AMBRA1 targets Elongin C for ubiquitination and degradation to modulate CRL5 signaling

Si Han Chen, Gwendolyn M. Jang, Ruth Hüttenhain, David E. Gordon, Dan Du, Billy W. Newton, Jeffrey R. Johnson, Joseph Hiatt, Judd Franklin Hultquist, Tasha L. Johnson, Yi Liang Liu, Lily A. Burton, Jordan Ye, Kurt M. Reichermeier, Robert M. Stroud, Alexander Marson, Jayanta Debnath, John D. Gross, Nevan J. Krogan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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 CRL4AMBRA 1 (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 CRL4AMBRA 1 is required to disrupt the assembly and attenuate the ligase activity of human CRL5SOCS 3 and HIV-1 CRL5VIF complexes as AMBRA1 depletion leads to hyperactivation of both CRL5 complexes. Moreover, CRL4AMBRA 1 modulates interleukin-6/STAT3 signaling and HIV-1 infectivity that are regulated by CRL5SOCS 3 and CRL5VIF, respectively. Thus, by discovering a substrate of CRL4AMBRA 1, ELOC, the shared adapter of CRL5 ubiquitin ligases, we uncovered a novel CRL cross-regulation pathway.

Original languageEnglish (US)
Article numbere97508
JournalEMBO Journal
Issue number18
StatePublished - Sep 14 2018


  • AMBRA1
  • HIV infection
  • cullin-RING ligase
  • interleukin-6
  • ubiquitin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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