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

  • Author(s): Chen, Si-Han;
  • Jang, Gwendolyn M;
  • Hüttenhain, Ruth;
  • Gordon, David E;
  • Du, Dan;
  • Newton, Billy W;
  • Johnson, Jeffrey R;
  • Hiatt, Joseph;
  • Hultquist, Judd F;
  • Johnson, Tasha L;
  • Liu, Yi-Liang;
  • Burton, Lily A;
  • Ye, Jordan;
  • Reichermeier, Kurt M;
  • Stroud, Robert M;
  • Marson, Alexander;
  • Debnath, Jayanta;
  • Gross, John D;
  • Krogan, Nevan J
  • et al.

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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.

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