ALS-linked loss of Cyclin-F function affects HSP90

• Verfasst von: Siebert, Alexander [VerfasserIn]
• Verfasst von: Gattringer, Vanessa [VerfasserIn]
• Verfasst von: Weishaupt, Jochen H. [VerfasserIn]
• Verfasst von: Behrends, Christian [VerfasserIn]
• Titel: ALS-linked loss of Cyclin-F function affects HSP90
• Verf.angabe: Alexander Siebert, Vanessa Gattringer, Jochen H. Weishaupt, Christian Behrends
• E-Jahr: 2022
• Jahr: 16 September, 2022
• Umfang: 17 S.
• Fussnoten: Gesehen am 26.06.2023
• Titel Quelle: Enthalten in: Life science alliance
• Ort Quelle: Heidelberg : EMBO Press, 2018
• Jahr Quelle: 2022
• Band/Heft Quelle: 5(2022), 12, Seite 1-17
• ISSN Quelle: 2575-1077
• DOI: doi:10.26508/lsa.202101359
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1850999031

Abstract

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.