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Open AccessArticle

Cytosolic Acidification Is the First Transduction Signal of Lactoferrin-Induced Regulated Cell Death Pathway

1
Laboratory of Oral Microbiology, University Clinic of Dentistry (CLUO), and Department of Functional Biology (Microbiology), Faculty of Medicine, University of Oviedo, 33006 Oviedo, Asturias, Spain
2
Present Address: Division of Infectious Diseases, Boston Children’s Hospital/Harvard Medical School, Boston, MA 02115, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(23), 5838; https://doi.org/10.3390/ijms20235838
Received: 30 October 2019 / Revised: 18 November 2019 / Accepted: 19 November 2019 / Published: 20 November 2019
(This article belongs to the Section Molecular Microbiology)
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. View Full-Text
Keywords: lactoferrin; Candida albicans; potassium efflux; cytosolic acidification; regulated cell death; apoptosis-like; cell signaling pathway lactoferrin; Candida albicans; potassium efflux; cytosolic acidification; regulated cell death; apoptosis-like; cell signaling pathway
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Andrés, M.T.; Acosta-Zaldívar, M.; González-Seisdedos, J.; Fierro, J.F. Cytosolic Acidification Is the First Transduction Signal of Lactoferrin-Induced Regulated Cell Death Pathway. Int. J. Mol. Sci. 2019, 20, 5838.

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