Abstract
In yeast, we reported the critical role of K+-efflux for the progress of the regulated cell death (RCD) induced by human lactoferrin (hLf), an antimicrobial protein of the innate immune system that blocks Pma1p H+-ATPase. In the present study, the K+ channel Tok1p was identified as the K+ channel-mediating K+-efflux, as indicated by the protective effect of extracellular K+ (≥30 mM), K+-channel blockers, and the greater hLf-resistance of TOK1-disrupted strains. K+-depletion was necessary but not sufficient to induce RCD as inferred from the effects of valinomycin, NH4Cl or nigericin which released a percentage of K+ similar to that released by lactoferrin without affecting cell viability. Cytosolic pH of hLf-treated cells decreased transiently (~0.3 pH units) and its inhibition prevented the RCD process, indicating that cytosolic acidification was a necessary and sufficient triggering signal. The blocking effect of lactoferrin on Pma1p H+-ATPase caused a transitory decrease of cytosolic pH, and the subsequent membrane depolarization activated the voltage-gated K+ channel, Tok1p, allowing an electrogenic K+-efflux. These ionic events, cytosolic accumulation of H+ followed by K+-efflux, constituted the initiating signals of this mitochondria-mediated cell death. These findings suggest, for the first time, the existence of an ionic signaling pathway in RCD.
Highlights
Human lactoferrin is an antimicrobial protein of the innate immune system that induces a regulated cell death (RCD) in Candida albicans, a commensal yeast that is an important human opportunistic pathogen [1,2,3]
HLf-induced RCD shares many of the apoptotic cell death characteristics observed in metazoan cells, and for this reason was previously identified as an apoptosis-like process [2,4]
We previously demonstrated that potassium efflux (K+-efflux) is a critical step for the progress of RCD induced by lactoferrin, as it is in higher eukaryotic cells [2]
Summary
Human lactoferrin (hLf) is an antimicrobial protein of the innate immune system that induces a regulated cell death (RCD) in Candida albicans, a commensal yeast that is an important human opportunistic pathogen [1,2,3]. Because the cytosolic accumulation of K+ depends on the electrochemical gradient generated by the plasma membrane Pma1p H+-ATPase, we hypothesized that the blocking effect of lactoferrin on this ATPase caused a sequential perturbation of ionic homeostasis [5,6,7] This ionic perturbation, which mainly included H+ and K+ ions, occurred at the cytoplasmic and mitochondrial level leading to regulated cell death. In this process, we reported the central role of mitochondria, ATP synthase, for the subsequent progress of RCD induced by lactoferrin [4,8]
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