PgmNr Y496: "Flipping the Switch": ROS-induced degradation of Med13 by SCFGrr1 mediates mitochondrial fragmentation and cell death.

Authors:
D. Stieg 1 ; S. Willis 1 ; J. Scuorzo 2 ; M. Song 2 ; K. Cooper 1


Institutes
1) Dept. of Molecular Biology, Rowan SOM, Stratford, NJ; 2) Dept. of Medicine, Rowan SOM, Stratford, NJ.


Keyword: Signal Transduction

Abstract:

In response to stress, the yeast1 and mammalian2 cyclin C translocate from the nucleus to the cytoplasm where it associates with the GTPase Drp1/Dnm1 to drive mitochondrial fragmentation and apoptosis. Therefore, the decision to release cyclin C represents a key life or death rubicon. In unstressed cells, the cyclin C-Cdk8 kinase regulates transcription by associating with the Mediator of RNA polymerase II. We previously reported that that the Mediator component Med13 anchors cyclin C in the nucleus3. Loss of Med13 function leads to constitutive cytoplasmic localization of cyclin C resulting in fragmented mitochondria, hypersensitivity to stress and mitochondrial dysfunction due to loss of mtDNA. Recently we showed that this molecular switch operates in a two step process. First, efficient cyclin C nuclear release requires its ROS-induced phosphorylation by the MAP kinase Slt24 in a carboxyl terminal region of cyclin C that includes a putative Med13 interaction site. Also, exposure of cells to high ROS damage activates the AMP kinase Snf1 that promotes cyclin C release through an indirect mechanism. The second step involves ROS-induced Med13 destruction by the SCFGrr1 ubiquitin ligase. Med13 associates with Grr1 in two-hybrid assays and SCF mediated degradation of Med13 requires active cyclin C-Cdk8. Taken together, these results indicate that the cell gauges damage severity by sequential activation of multiple signaling pathways. These results are consistent with a model in which cyclin C phosphorylation permits its disassociation from Med13 and that Med13 destruction allows full cyclin C release and prevents reaccumulation of the cyclin in the nucleus.

1Dev. Cell. 2014, 28:161; 2Mol. Biol. Cell. 2015, 26:1030; 3Mol. Biol. Cell, 2104 25:2807; 4Mol. Biol. Cell. 2014, 25:1396.Grant support W.W. Smith Charitable Trust (CO 604) and NIH R15-113196 to K.F.C.



Yeast Database Genetic Index
1. gene symbol: MED13; systematic name: YDR443C
2. gene symbol: CNC1; systematic name: YNL025C
3. gene symbol: SNF1; systematic name: YDR477W
4. gene symbol: DNM1; systematic name: YLL001W
5. gene symbol: SLT2; systematic name: YHR030C
6. gene symbol: CDK8; systematic name: YPL042C