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Review
. 2021 Oct 15;9(10):2152.
doi: 10.3390/microorganisms9102152.

Cdk8 Kinase Module: A Mediator of Life and Death Decisions in Times of Stress

Brittany Friedson  1 , Katrina F Cooper  1
Affiliations
Review

Cdk8 Kinase Module: A Mediator of Life and Death Decisions in Times of Stress

Brittany Friedson et al. Microorganisms. .

Abstract

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 S. cerevisiae, 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.

Keywords: Med13; ROS and nutrient signaling; autophagy; cellular stress; cyclin C; hyper-fission; mitochondrial dynamics; proteasome; regulated cell death.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Top panel: Model outlining the different mechanisms used by the CKM to relieve repression on SRG’s in response to either cell death (oxidative stress) or cell survival (nitrogen starvation) cues in yeast. Bottom panel: Live fluorescence images of cyclin C-YFP and DS-Red tagged mitochondria demonstrating the different phenotypes observed after 2 h treatment with H2O2 (left) or following nitrogen starvation (SD-N—right). CKM-Cdk8 kinase module, SRG’s—stress response genes, YFP—yellow fluorescence protein.
Figure 2
Figure 2
Model of the interaction of the CKM with the core mediator complex and RNA Pol II. (A). In unstressed cells, the CKM associates with the Mediator at UAS sites found in promotors, by the interaction of Med13 with the mediator hook. This inhibits the Mediator-RNA pol II interaction, preventing PIC formation and transcription of mRNA. Following stress, the CKM is released from the Mediator, permitting PIC assembly and transcription of mRNA. Additional repressors and/or activators also mediate transcription by binding to UAS motifs (Upstream Activating Sequence). Adapted from Cherji et al (2017). NAC. PMID:28575439. (B) Structure of the yeast CKM determined by cryo-EM and mass spectrometry. Reproduced with permission from Li et al (2021) Scientific Advances. PMID: 33390853. CKM—Cdk8 kinase module, RNA Pol II—RNA polymerase II, PIC—preinitiation complex, Å—Angstrom.
Figure 3
Figure 3
Outline of the Cell Wall Integrity (CWI) signal transduction pathway that mediates cyclin C translocation to the cytoplasm following low oxidative stress (0.4 mM H2O2). Both the MAPK of this pathway (Slt2) and its pseudo-kinase partner, Kdx1 are required for the efficient export and degradation of cyclin C. Cyclin C release is dependent upon Med13 degradation by the SCFGrr1 E3 ligase complex, triggered by Cdk8, Slt2 and the AMPK Snf1-mediated phosphorylation. Following high levels of oxidative stress (1.2 mM H2O2) the activity of Ste11, the MAPKKK of the HOG signal transduction pathway is also required. For clarity, Ask10 and Plc1, which also play roles in cyclin C’s fate are omitted from the figure. MAPK—mitogen activated protein kinase, SCF—Skp1-Cullin-F-box-protein, HOG—high osmolarity glycerol, AMPK—adenosine monophosphate-activated protein kinase, P—phosphorylation event.
Figure 4
Figure 4
Upper panel: Outline of the Snx4-assisted autophagy pathway of transcription factors. This pathway transports Med13 from the nucleus to the vacuole for proteolysis following TORC1 inhibition. NPC—nuclear pore complex, PAS—Pre-autophagosomal structure.
Figure 5
Figure 5
Outline of the different mitochondrial dynamics observed in unstressed and ROS (Reactive oxygen species)-treated yeast cells. See text for details. The fluorescence images are of budding yeast harboring a Mt-DSRed plasmid that localizes to the OMM (outer mitochondrial membrane). MOMP—mitochondria outer membrane permeabilization, RCD—regulated cell death.
Figure 6
Figure 6
Similarities and differences between cyclin C and Med13’s state following stress. See text for details. SRG—stress response genes, UPS—ubiquitin proteasome system.
See this image and copyright information in PMC

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References

    1. Towers C.G., Wodetzki D., Thorburn A. Autophagy and cancer: Modulation of cell death pathways and cancer cell adaptations. J. Cell Biol. 2020;219:e201909033. doi: 10.1083/jcb.201909033. - DOI - PMC - PubMed
    1. Madeo F., Frohlich E., Ligr M., Grey M., Sigrist S.J., Wolf D.H., Frohlich K.U. Oxygen stress: A regulator of apoptosis in yeast. J. Cell Biol. 1999;145:757–767. doi: 10.1083/jcb.145.4.757. - DOI - PMC - PubMed
    1. Galluzzi L., Baehrecke E.H., Ballabio A., Boya P., Bravo-San Pedro J.M., Cecconi F., Choi A.M., Chu C.T., Codogno P., Colombo M.I., et al. Molecular definitions of autophagy and related processes. EMBO J. 2017;36:1811–1836. doi: 10.15252/embj.201796697. - DOI - PMC - PubMed
    1. Cooper K.F. Till Death Do Us Part: The Marriage of Autophagy and Apoptosis. Oxid. Med. Cell. Longev. 2018;2018:4701275. doi: 10.1155/2018/4701275. - DOI - PMC - PubMed
    1. Carmona-Gutierrez D., Bauer M.A., Zimmermann A., Aguilera A., Austriaco N., Ayscough K., Balzan R., Bar-Nun S., Barrientos A., Belenky P., et al. Guidelines and recommendations on yeast cell death nomenclature. Microb. Cell. 2018;5:4–31. doi: 10.15698/mic2018.01.607. - DOI - PMC - PubMed

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