2. Academic Validation
  3. CRL4AMBRA1 targets Elongin C for ubiquitination and degradation to modulate CRL5 signaling

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

  • EMBO J. 2018 Sep 14;37(18):e97508. doi: 10.15252/embj.201797508.
Si-Han Chen 1 2 3 4,  Gwendolyn M Jang 1 3 4,  Ruth Hüttenhain 1 3 4,  David E Gordon 1 3 4,  Dan Du 5,  Billy W Newton 1 3 4,  Jeffrey R Johnson 1 3 4,  Joseph Hiatt 6 7 8 9,  Judd F Hultquist 1 3 4,  Tasha L Johnson 1 3 4,  Yi-Liang Liu 10,  Lily A Burton 11,  Jordan Ye 12 13,  Kurt M Reichermeier 14,  Robert M Stroud 3 10,  Alexander Marson 3 8 9 15 16 17,  Jayanta Debnath 12 13,  John D Gross 3 11,  Nevan J Krogan 18 3 4 13
Affiliations

Affiliations

  • 1 Department of Cellular and Molecular Pharmacology, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA, USA.
  • 2 Biophysics Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
  • 3 Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA.
  • 4 Gladstone Institutes, San Francisco, CA, USA.
  • 5 Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.
  • 6 Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA, USA.
  • 7 Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
  • 8 Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
  • 9 Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
  • 10 Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
  • 11 Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
  • 12 Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
  • 13 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • 14 California Institute of Technology, Pasadena, CA, USA.
  • 15 Division of Infectious Diseases and Rheumatology, University of California, Berkeley, Berkeley, CA, USA.
  • 16 Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
  • 17 Chan Zuckerberg Biohub, San Francisco, CA, USA.
  • 18 Department of Cellular and Molecular Pharmacology, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA, USA [email protected].
PMID: 30166453 DOI: 10.15252/embj.201797508
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.

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