CRL4AMBRA1 targets Elongin C for ubiquitination and degradation to modulate CRL5 signaling.
- 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.
Published Web Location
https://www.ncbi.nlm.nih.gov/pubmed/?term=30166453%5Buid%5DAbstract
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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