Adaptive exchange sustains cullin-RING ubiquitin ligase networks and proper licensing of DNA replication

Cop9 signalosome (CSN) regulates the function of cullin-RING E3 ubiquitin ligases (CRLs) by deconjugating the ubiquitin-like protein NEDD8 from the cullin subunit. To understand the physiological impact of CSN function on the CRL network and cell proliferation, we combined quantitative mass spectrom...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 36; p. e2205608119
Main Authors:	Zhang, Yaru, Jost, Marco, Pak, Ryan A, Lu, Daniel, Li, Jing, Lomenick, Brett, Garbis, Spiros D, Li, Chi-Ming, Weissman, Jonathan S, Lipford, James Russell, Deshaies, Raymond J
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 06-09-2022
Subjects:	Adenomatous polyposis coli Azepines - metabolism Biological Sciences Cell proliferation Cell Survival Cell viability COP9 Signalosome Complex - antagonists & inhibitors COP9 Signalosome Complex - genetics COP9 Signalosome Complex - metabolism CRISPR Cullin Cullin Proteins - genetics Cullin Proteins - metabolism DNA biosynthesis DNA Replication Genomes Imidazoles - metabolism Mass spectrometry Mass spectroscopy NEDD8 Protein - metabolism Pyrazoles - metabolism Receptor mechanisms Substrates Toxicity Ubiquitin Ubiquitin-protein ligase Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism CSN5i-3 CRISPR screen Cop9 signalosome DNA replication deneddylation
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Summary:	Cop9 signalosome (CSN) regulates the function of cullin-RING E3 ubiquitin ligases (CRLs) by deconjugating the ubiquitin-like protein NEDD8 from the cullin subunit. To understand the physiological impact of CSN function on the CRL network and cell proliferation, we combined quantitative mass spectrometry and genome-wide CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) screens to identify factors that modulate cell viability upon inhibition of CSN by the small molecule CSN5i-3. CRL components and regulators strongly modulated the antiproliferative effects of CSN5i-3, and in addition we found two pathways involved in genome integrity, SCF -APC/C-GMNN and CUL4 -SETD8, that contribute substantially to the toxicity of CSN inhibition. Our data highlight the importance of CSN-mediated NEDD8 deconjugation and adaptive exchange of CRL substrate receptors in sustaining CRL function and suggest approaches for leveraging CSN inhibition for the treatment of cancer.
Bibliography:	Author contributions: Y.Z., J.R.L., and R.J.D. designed research; Y.Z., M.J., R.A.P., D.L., and J.L. performed research; Y.Z., M.J., R.A.P., D.L., J.L., B.L., S.D.G., C.-M.L., and J.S.W. contributed new reagents/analytic tools; Y.Z., M.J., D.L., B.L., S.D.G., C.-M.L., and J.S.W. analyzed data; Y.Z. and R.J.D. wrote the paper; and R.J.D. supervised the research. 3Present address: Proteas Bioanalytics Inc., Torrance, CA 90502. Contributed by Raymond Deshaies; received April 6, 2022; accepted June 24, 2022; reviewed by Jean Cook and Michele Pagano 4Present address: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02139. 1Present address: Department of Microbiology, Harvard Medical School, Boston, MA 02115. 2Present address: Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.2205608119