CRL4AMBRA1 targets Elongin C for ubiquitination and degradation to modulate CRL5 signaling期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

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

Authors:	Si‐Han Chen Gwendolyn M Jang Ruth Hüttenhain David E Gordon Dan Du Billy W Newton Jeffrey R Johnson Joseph Hiatt Judd F 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

Affiliation:	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

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 CRL4^AMBRA¹ (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 CRL4^AMBRA¹ is required to disrupt the assembly and attenuate the ligase activity of human CRL5^SOCS³ and HIV‐1 CRL5^VIF complexes as AMBRA1 depletion leads to hyperactivation of both CRL5 complexes. Moreover, CRL4^AMBRA¹ modulates interleukin‐6/STAT3 signaling and HIV‐1 infectivity that are regulated by CRL5^SOCS³ and CRL5^VIF, respectively. Thus, by discovering a substrate of CRL4^AMBRA¹, ELOC, the shared adapter of CRL5 ubiquitin ligases, we uncovered a novel CRL cross‐regulation pathway.

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

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