Sirtuin 5 Is Regulated by the SCF Cyclin F Ubiquitin Ligase and Is Involved in Cell Cycle Control

• Published in: Molecular and cellular biology Vol. 41; no. 2
• Main Authors: Mills, Christine A, Wang, Xianxi, Bhatt, Dhaval P, Grimsrud, Paul A, Matson, Jacob Peter, Lahiri, Debojyoti, Burke, Daniel J, Cook, Jeanette Gowen, Hirschey, Matthew D, Emanuele, Michael J
• Format: Journal Article
• Language: English
• Published: United States 01.02.2021
• Subjects: Cell Cycle - genetics; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; F-Box Proteins - genetics; F-Box Proteins - metabolism; Gene Expression Profiling; Gene Expression Regulation, Fungal; Genes, Lethal; HEK293 Cells; HeLa Cells; Humans; Mutation; Protein Processing, Post-Translational; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Signal Transduction; Sirtuins - genetics; Sirtuins - metabolism; SKP Cullin F-Box Protein Ligases - genetics; SKP Cullin F-Box Protein Ligases - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; metabolism; sirtuin 5 (SIRT5); cell cycle; ubiquitin; SCF; cyclin F (CCNF)
• ISSN: 1098-5549; 1098-5549
• DOI: 10.1128/MCB.00269-20

The ubiquitin-proteasome system is essential for cell cycle progression. Cyclin F is a cell cycle-regulated substrate adapter F-box protein for the kp1, UL1, and -box protein (SCF) family of E3 ubiquitin ligases. Despite its importance in cell cycle progression, identifying cyclin F-bound SCF complex (SCF ) substrates has remained challenging. Since cyclin F overexpression rescues a yeast mutant in the 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 G population and a subsequent increase in both S and G /M. Global proteomic analyses reveal cyclin-dependent kinase (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.