Friedson Brittany, Cooper Katrina F
Department of Molecular Biology, Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ 08084, USA.
Microorganisms. 2021 Oct 15;9(10):2152. doi: 10.3390/microorganisms9102152.
The Cdk8 kinase module (CKM) of the multi-subunit mediator complex plays an essential role in cell fate decisions in response to different environmental cues. In the budding yeast , the CKM consists of four conserved subunits (cyclin C and its cognate cyclin-dependent kinase Cdk8, Med13, and Med12) and predominantly negatively regulates a subset of stress responsive genes (SRG's). Derepression of these SRG's is accomplished by disassociating the CKM from the mediator, thus allowing RNA polymerase II-directed transcription. In response to cell death stimuli, cyclin C translocates to the mitochondria where it induces mitochondrial hyper-fission and promotes regulated cell death (RCD). The nuclear release of cyclin C requires Med13 destruction by the ubiquitin-proteasome system (UPS). In contrast, to protect the cell from RCD following SRG induction induced by nutrient deprivation, cyclin C is rapidly destroyed by the UPS before it reaches the cytoplasm. This enables a survival response by two mechanisms: increased ATP production by retaining reticular mitochondrial morphology and relieving CKM-mediated repression on autophagy genes. Intriguingly, nitrogen starvation also stimulates Med13 destruction but through a different mechanism. Rather than destruction via the UPS, Med13 proteolysis occurs in the vacuole (yeast lysosome) via a newly identified Snx4-assisted autophagy pathway. Taken together, these findings reveal that the CKM regulates cell fate decisions by both transcriptional and non-transcriptional mechanisms, placing it at a convergence point between cell death and cell survival pathways.
多亚基中介体复合物的Cdk8激酶模块（CKM）在响应不同环境信号的细胞命运决定中起关键作用。在芽殖酵母中，CKM由四个保守亚基组成（细胞周期蛋白C及其同源的细胞周期蛋白依赖性激酶Cdk8、Med13和Med12），主要对一部分应激反应基因（SRG）进行负调控。这些SRG的去抑制是通过使CKM与中介体解离来实现的，从而允许RNA聚合酶II指导的转录。响应细胞死亡刺激时，细胞周期蛋白C会转位至线粒体，在那里它会诱导线粒体过度分裂并促进程序性细胞死亡（RCD）。细胞周期蛋白C的核释放需要泛素-蛋白酶体系统（UPS）破坏Med13。相反，为了在营养剥夺诱导SRG后保护细胞免于RCD，细胞周期蛋白C在到达细胞质之前会被UPS迅速降解。这通过两种机制实现存活反应：通过保持网状线粒体形态增加ATP生成，并解除CKM对自噬基因的介导抑制。有趣的是，氮饥饿也会刺激Med13的降解，但通过不同的机制。Med13的蛋白水解不是通过UPS进行破坏，而是通过新发现的Snx4辅助自噬途径在液泡（酵母溶酶体）中发生。综上所述，这些发现揭示CKM通过转录和非转录机制调节细胞命运决定，使其处于细胞死亡和细胞存活途径的交汇点。
