The E3 Ubiquitin Ligase SCF Cyclin F Promotes Sequestosome-1/p62 Insolubility and Foci Formation and is Dysregulated in ALS and FTD Pathogenesis.

ABSTRACT: Amyotrophic lateral sclerosis (ALS)- and frontotemporal dementia (FTD)-linked mutations in CCNF have been shown to cause dysregulation to protein homeostasis. CCNF encodes for cyclin F, which is part of the cyclin F-E3 ligase complex SCF^cyclinF known to ubiquitylate substrates for proteasomal degradation. In this study, we identified a function of cyclin F to regulate substrate solubility and show how cyclin F mechanistically underlies ALS and FTD disease pathogenesis. We demonstrated that ALS and FTD-associated protein sequestosome-1/p62 (p62) was a canonical substrate of cyclin F which was ubiquitylated by the SCF^cyclinF complex. We found that SCF^{cyclin F} ubiquitylated p62 at lysine(K)281, and that K281 regulated the propensity of p62 to aggregate. Furthe

SUBMITTER: Davidson JM 

PROVIDER: S-EPMC10415446 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature