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

Authors:
Publisher website
Google Scholar
Abstract
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.
Funding Information
  • National Institutes of Health (RO1GM120309)
  • National Institutes of Health (RO1GM134231)
  • National Institutes of Health (T32 DK007731)
  • National Institutes of Health (R01AG045351)
  • National Science Foundation (DGE1144081)
  • American Cancer Society (RSG-18-220-01-TBG)
  • Glenn Foundation for Medical Research

This publication has 68 references indexed in Scilit: