SCFCyclin F targets the metabolic protein Sirtuin 5 for ubiquitination

Cell cycle transitions are regulated by a number of coordinating signaling events. The ubiquitin-proteasome system is an important part of this cell cycle signaling. Cyclin F, a substrate adapter for the SCF (SKP1/CUL1/F-box) E3 ubiquitin ligase, is an important regulator of cell cycle progression. However, identifying SCFCyclin F substrates important for the G1-S transition and other cell cycle events has remained technically challenging. Since Cyclin F overexpression rescues a yeast mutant in the cdc4 gene, we considered the possibility that other genes that genetically modify cdc4 mutant lethality could also encode Cyclin F substrates. We identified the mitochondrial and cytosolic deacylating enzyme Sirtuin 5 (SIRT5) as a novel Cyclin F substrate. SIRT5 has been implicated in a number of metabolic processes, but its connection to the cell cycle is not known. Here, we demonstrate the ability of Cyclin F to interact with, ubiquitinate and control the abundance and stability of SIRT5. Since previously identified Cyclin F targets are important for cell cycle progression, we hypothesized that SIRT5 would influence cell cycle progression. We show SIRT5 CRISPR knockout results in a diminished G1 population, and subsequent increase in both S and G2/M. Proteomic analyses reveal CDK signaling changes congruent with the cell cycle changes in SIRT5 knockout cells. Together these data demonstrate SIRT5 is regulated by Cyclin F and suggest a connection between SIRT5, cell cycle regulation, and metabolism.