ALS-linked loss of Cyclin-F function affects HSP90
The founding member of the F-box protein family, Cyclin-F, serves as a substrate adaptor for the E3 ligase Skp1-Cul1-F-box (SCF)Cyclin-F which is responsible for ubiquitination of proteins involved in cell cycle progression, DNA damage and mitotic fidelity. Missense mutations in CCNF encoding for Cy...
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| Hauptverfasser: | , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
16 September, 2022
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| In: |
Life science alliance
Year: 2022, Jahrgang: 5, Heft: 12, Pages: 1-17 |
| ISSN: | 2575-1077 |
| DOI: | 10.26508/lsa.202101359 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.26508/lsa.202101359 Verlag, kostenfrei, Volltext: https://www.life-science-alliance.org/content/5/12/e202101359 
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| Verfasserangaben: | Alexander Siebert, Vanessa Gattringer, Jochen H. Weishaupt, Christian Behrends |
| Zusammenfassung: | The founding member of the F-box protein family, Cyclin-F, serves as a substrate adaptor for the E3 ligase Skp1-Cul1-F-box (SCF)Cyclin-F which is responsible for ubiquitination of proteins involved in cell cycle progression, DNA damage and mitotic fidelity. Missense mutations in CCNF encoding for Cyclin-F are associated with amyotrophic lateral sclerosis (ALS). However, it remains elusive whether CCNF mutations affect the substrate adaptor function of Cyclin-F and whether altered SCFCyclin-F-mediated ubiquitination contributes to pathogenesis in CCNF mutation carriers. To address these questions, we set out to identify new SCFCyclin-F targets in neuronal and ALS patient-derived cells. Mass spectrometry-based ubiquitinome profiling of CCNF knockout and mutant cell lines as well as Cyclin-F proximity and interaction proteomics converged on the HSP90 chaperone machinery as new substrate candidate. Biochemical analyses provided evidence for a Cyclin-F-dependent association and ubiquitination of HSP90AB1 and implied a regulatory role that could affect the binding of a number of HSP90 clients and co-factors. Together, our results point to a possible Cyclin-F loss-of-function-mediated chaperone dysregulation that might be relevant for ALS. |
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| Beschreibung: | Gesehen am 26.06.2023 |
| Beschreibung: | Online Resource |
| ISSN: | 2575-1077 |
| DOI: | 10.26508/lsa.202101359 |