Suchergebnisse

Iron acquisition systems have to be tightly regulated to assure a continuous supply of iron, since it is essential for survival, but simultaneously to prevent iron overload that is toxic to the cells. In budding yeast, the low‑iron sensing transcription factor Aft1p is a master regulator of the iron regulon. Our previous work revealed that bioactive sphingolipids modulate iron homeostasis as yeast cells lacking the sphingomyelinase Isc1p exhibit an upregulation of the iron regulon. In this study, we show that Isc1p impacts on iron accumulation and localization. Notably, Aft1p is activated in isc1Δ cells due to a decrease in its phosphorylation and an increase in its nuclear levels. Consistently, the expression of a phosphomimetic version of Aft1p-S210/S224 that favours its nuclear export abolished iron accumulation in isc1Δ cells. Notably, the Hog1p kinase, homologue of mammalian p38, interacts with and directly phosphorylates Aft1p at residues S210 and S224. However, Hog1p-Aft1p interaction decreases in isc1Δ cells, which likely contributes to Aft1p dephosphorylation and consequently to Aft1p activation and iron overload in isc1Δ cells. These results suggest that alterations in sphingolipid composition in isc1Δ cells may impact on iron homeostasis by disturbing the regulation of Aft1p by Hog1p. To our knowledge, Hog1p is the first kinase reported to directly regulate Aft1p, impacting on iron homeostasis. ; This article is a result of the project Norte-01-0145-FEDER-000008 - Porto Neurosciences and Neurologic Disease Research Initiative at I3S supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). CP was supported by Fundo Social Europeu and Programa Operacional Potencial Humano through FCT investigator grant IF/00889/2015. FP and EdN lab is supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2015-64437-P and FEDER to FP; BFU2014-52333-P and FEDER to EN), the Catalan Government (2014 SGR 599 to FP and EN) and by Fundación Botín, by Banco Santander through its Santander Universities Global Division to FP. FP is recipient of an ICREA Acadèmia (Generalitat de Catalunya).