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

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

doi:10.15252/embj.201797508

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.

Authors

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 Du⁵, 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 Liu¹⁰, Lily A Burton¹¹, Jordan Ye^{12

13}, Kurt M Reichermeier¹⁴, 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

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 nevan.krogan@ucsf.edu.

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; 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
IL17RB protein, human
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

Abstract

Publication types

MeSH terms

Substances

Grants and funding