Open AccessSirtuin 5 Is Regulated by the SCFCyclin F Ubiquitin Ligase and Is Involved in Cell Cycle Control
Author(s) -
Christine A. Mills,
Xianxi Wang,
Dhaval P. Bhatt,
Paul A. Grimsrud,
Jacob P. Matson,
Debojyoti Lahiri,
Daniel J. Burke,
Jeanette Gowen Cook,
Matthew D. Hirschey,
Michael J. Emanuele
Publication year - 2021
Publication title -
molecular and cellular biology (print)
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.00269-20
Subject(s) - biology , cell division control protein 4 , cell cycle , cyclin a2 , f box protein , ubiquitin ligase , cyclin a , microbiology and biotechnology , cyclin dependent kinase , cyclin d , cyclin dependent kinase complex , skp1 , cyclin , cyclin e , ubiquitin , biochemistry , cell , gene
The ubiquitin-proteasome system is essential for cell cycle progression. Cyclin F is a cell cycle-regulated substrate adapter F-box protein for the S kp1, C UL1, and F -box protein (SCF) family of E3 ubiquitin ligases. Despite its importance in cell cycle progression, identifying cyclin F-bound SCF complex (SCF Cyclin 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 G 1 population and a subsequent increase in both S and G 2 /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.