ALS-linked loss of Cyclin-F function affects HSP90

Life Sci Alliance. 2022 Sep 16;5(12):e202101359. doi: 10.26508/lsa.202101359.


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)<sup>Cyclin-F</sup> which is responsible for ubiquitination of proteins involved in cell cycle progression, DNA damage and mitotic fidelity. Missense mutations in <i>CCNF</i> encoding for Cyclin-F are associated with amyotrophic lateral sclerosis (ALS). However, it remains elusive whether <i>CCNF</i> mutations affect the substrate adaptor function of Cyclin-F and whether altered SCF<sup>Cyclin-F</sup>-mediated ubiquitination contributes to pathogenesis in <i>CCNF</i> mutation carriers. To address these questions, we set out to identify new SCF<sup>Cyclin-F</sup> targets in neuronal and ALS patient-derived cells. Mass spectrometry-based ubiquitinome profiling of <i>CCNF</i> 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • Cyclins* / genetics
  • Cyclins* / metabolism
  • F-Box Proteins* / genetics
  • HSP90 Heat-Shock Proteins* / genetics
  • Humans
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination


  • CCNF protein, human
  • Cyclins
  • F-Box Proteins
  • HSP90 Heat-Shock Proteins
  • Ubiquitin-Protein Ligases