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, 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 G₁ population and a subsequent increase in both S and G₂/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.

中文翻译：

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Sirtuin 5 由 SCFCyclin F 泛素连接酶调节并参与细胞周期控制

泛素-蛋白酶体系统对细胞周期进程至关重要。Cyclin F 是E3 泛素连接酶的S kp1、C UL1 和F -box蛋白 (SCF) 家族的细胞周期调节底物接头 F-box 蛋白。尽管它在细胞周期进程中很重要，但识别 cyclin F 结合的 SCF 复合物 (SCF ^{Cyclin F} ) 底物仍然具有挑战性。由于细胞周期蛋白 F 过表达拯救了cdc4 中的酵母突变体基因，我们考虑了其他基因修饰 cdc4 突变体致死率的基因也可以编码细胞周期蛋白 F 底物的可能性。我们将线粒体和细胞溶质去酰化酶 sirtuin 5 (SIRT5) 鉴定为一种新的细胞周期蛋白 F 底物。SIRT5 与代谢过程有关，但它与细胞周期的联系尚不清楚。我们表明，cyclin F 与 SIRT5 的泛素化、丰度和稳定性相互作用并对其进行控制。我们显示 SIRT5 敲除导致 G ₁种群减少，随后 S 和 G ₂均增加/米。全球蛋白质组学分析揭示细胞周期蛋白依赖性激酶 (CDK) 信号变化与 SIRT5 敲除细胞中的细胞周期变化一致。总之，这些数据表明 SIRT5 受细胞周期蛋白 F 的调节，并表明 SIRT5、细胞周期调节和新陈代谢之间存在联系。