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Vol. 17, Issue 8, 3409-3422, August 2006

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Multiple Signaling Pathways Regulate Yeast Cell Death during the Response to Mating Pheromones

Nan-Nan Zhang^*, Drew D. Dudgeon^*, Saurabh Paliwal, Andre Levchenko, Eric Grote, and Kyle W. Cunningham^*

*Department of Biology and Whitaker Institute for Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218; and Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205

Submitted March 6, 2006; Revised May 8, 2006; Accepted May 18, 2006
Monitoring Editor: Daniel Lew

Mating pheromones promote cellular differentiation and fusion of yeast cells with those of the opposite mating type. In the absence of a suitable partner, high concentrations of mating pheromones induced rapid cell death in 25% of the population of clonal cultures independent of cell age. Rapid cell death required Fig1, a transmembrane protein homologous to PMP-22/EMP/MP20/Claudin proteins, but did not require its Ca²⁺ influx activity. Rapid cell death also required cell wall degradation, which was inhibited in some surviving cells by the activation of a negative feedback loop involving the MAP kinase Slt2/Mpk1. Mutants lacking Slt2/Mpk1 or its upstream regulators also underwent a second slower wave of cell death that was independent of Fig1 and dependent on much lower concentrations of pheromones. A third wave of cell death that was independent of Fig1 and Slt2/Mpk1 was observed in mutants and conditions that eliminate calcineurin signaling. All three waves of cell death appeared independent of the caspase-like protein Mca1 and lacked certain "hallmarks" of apoptosis. Though all three waves of cell death were preceded by accumulation of reactive oxygen species, mitochondrial respiration was only required for the slowest wave in calcineurin-deficient cells. These findings suggest that yeast cells can die by necrosis-like mechanisms during the response to mating pheromones if essential response pathways are lacking or if mating is attempted in the absence of a partner.

Address correspondence to: Kyle W. Cunningham ( kwc{at}jhu.edu)

Abbreviations used: CN, calcineurin; CWI, cell wall integrity; CYC, cytochrome c; MPK, mitogen-activate protein kinase; PCD, programmed cell death; ROS, reactive oxygen species.

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