CRL4 AMBRA1 targets Elongin C for ubiquitination and degradation to modulate CRL5 signaling

EMBO J. 2018 Sep 14;37(18):e97508. doi: 10.15252/embj.201797508. Epub 2018 Aug 30.

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.

Keywords: AMBRA1; HIV infection; cullin‐RING ligase; interleukin‐6; ubiquitin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Elongin / genetics
  • Elongin / metabolism*
  • HEK293 Cells
  • HIV Infections / genetics
  • HIV Infections / metabolism*
  • HIV-1 / genetics
  • HIV-1 / metabolism*
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Proteolysis*
  • Signal Transduction*
  • Suppressor of Cytokine Signaling 3 Protein / genetics
  • Suppressor of Cytokine Signaling 3 Protein / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination*
  • vif Gene Products, Human Immunodeficiency Virus / genetics
  • vif Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • AMBRA1 protein, human
  • Adaptor Proteins, Signal Transducing
  • ELOC protein, human
  • Elongin
  • IL6 protein, human
  • Interleukin-6
  • SOCS3 protein, human
  • Suppressor of Cytokine Signaling 3 Protein
  • vif Gene Products, Human Immunodeficiency Virus
  • vif protein, Human immunodeficiency virus 1
  • Ubiquitin-Protein Ligases
  • CRL4 protein, human