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PreprintCited by 5Ubiquitin and proteasome pathwaysProtein Degradation and InhibitorsMicrotubule and mitosis dynamics

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The C-terminal tail of CSNAP attenuates the CSN complex

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Füzesi-Levi, Maria G., Ben-Nissan, Gili, Listov, Dina, Hayouka, Zvi, Fleishman, Sarel, Sharon, Michal·2022·Life Science Alliance
DOI 10.1101/2022.07.18.500399PMC PMC10355216

Preprint — published as 10.26508/lsa.202201634 · Paper page

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Abstract

Protein degradation is one of the essential mechanisms that enables reshaping of the proteome landscape in response to various stimuli. The largest E3 ubiquitin ligase family that targets proteins to degradation by catalyzing ubiquitnation is the cullin-RING ligases (CRL). Many of the proteins that are regulated by CRLs are central to tumorigenesis and tumour progression, and dysregulation of the CRL family is frequently associated with cancer. The CRL family comprises ∼300 complexes all of which are regulated by the COP9 signalosome complex (CSN). Therefore, the CSN is considered an attractive target for therapeutic intervention. Research efforts for targeted CSN inhibition have been directed towards inhibition of the complex enzymatic subunit, CSN5. Here, we have taken a fresh approach focusing on CSNAP, the smallest CSN subunit. Our results show that the C-terminal region of CSNAP is tightly packed within the CSN complex, in a groove formed by CSN3 and CSN8. We show that a 16 amino acid C-terminal peptide, derived from this CSN interacting region, can displace the endogenous CSNAP subunit from the complex. This, in turn, leads to a CSNAP null phenotype that attenuates CSN activity and consequently CRLs function. Overall, our findings emphasize the potential of a CSNAP-based peptide for CSN inhibition as a new therapeutic avenue.

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Metadata

Authors
Füzesi-Levi, M. G., Ben-Nissan, G., Listov, D., Hayouka, Z., Fleishman, S., & Sharon, M.
Affiliations
  • Weizmann Institute of Science (IL)
  • Hebrew University of Jerusalem (IL)
Corresponding author
Sharon, Michal
ORCID
Venue
Life Science Alliance
Publisher
openRxiv
Published
2022-07-19
Volume
6
Issue
10
Pages
e202201634-e202201634
ISSN
2575-1077 (ISSN-L)
DOI
10.1101/2022.07.18.500399
PMC
PMC10355216
OpenAlex
W4384627408
Cited by
5
References
1
Citations by year
2026: 3 · 2025: 2
FWCI
0.44
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Life Science Alliance (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
Keywords
COP9 signalosome, C-terminal tail, cullin-RING ligases, E3 ubiquitin ligase, CSN3, protein degradation, cancer therapy
MeSH terms
COP9 Signalosome Complex, Phenotype, Ubiquitin-Protein Ligases, Ubiquitination

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