Sirtuin 5 is Regulated by the SCF-Cyclin F Ubiquitin Ligase and is Involved in Cell Cycle Control.
The ubiquitin-proteasome system is essential for cell cycle progression. Cyclin F is a cell cycle regulated substrate adapter F-box protein for the SKP1/CUL1/F-box (SCF) family of E3 ubiquitin ligases. Despite its importance in cell cycle progression, identifying SCFCyclin F substrates has remained 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 metabolic processes, but its connection to the cell cycle is not known. We show that Cyclin F interacts with, and controls the ubiquitination, abundance, and stability of SIRT5. We show SIRT5 knockout results in a diminished G1 population, and subsequent increase in both S and G2/M. Global proteomic analyses reveal CDK signaling changes congruent with the cell cycle changes in SIRT5 knockout cells. Together these data demonstrate that SIRT5 is regulated by Cyclin F and suggest a connection between SIRT5, cell cycle regulation, and metabolism.
Mills, CA; Wang, X; Bhatt, DP; Grimsrud, PA; Matson, JP; Lahiri, D; Burke, DJ; Cook, JG; Hirschey, MD; Emanuele, MJ
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