title: The ceramide-activated protein phosphatase Sit4p controls lifespan, mitochondrial function and cell cycle progression by regulating hexokinase 2 phosphorylation.
abstract: Sit4p is the catalytic subunit of a ceramide-activated PP2A-like phosphatase that regulates cell cycle, mitochondrial function, oxidative stress resistance and chronological lifespan in yeast. In this study, we show that hexokinase 2 (Hxk2p) is hyperphosphorylated in sit4Δ mutants grown in glucose medium by a Snf1p-independent mechanism and Hxk2p-S15A mutation suppresses phenotypes associated with SIT4 deletion, namely growth arrest at G1 phase, derepression of mitochondrial respiration, H2O2 resistance and lifespan extension. Consistently, the activation of Sit4p in isc1Δ mutants, which has been associated with premature aging, leads to Hxk2p hypophosphorylation, and the expression of Hxk2p-S15E increases the lifespan of isc1Δ cells. The overall results suggest that Hxk2p functions downstream of Sit4p in the control of cell cycle, mitochondrial function, oxidative stress resistance and chronological lifespan.
authors.affiliation: b IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto , Porto , Portugal.|c ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Departamento de Biologia Molecular, Universidade do Porto , Porto , Portugal.
authors.forename: António Daniel
authors.initials: AD
authors.lastname: Barbosa
authors.affiliation: a Instituto de Investigação e Inovação em Saúde, Universidade do Porto , Porto , Portugal.|b IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto , Porto , Portugal.
authors.forename: Clara
authors.initials: C
authors.lastname: Pereira
authors.affiliation: a Instituto de Investigação e Inovação em Saúde, Universidade do Porto , Porto , Portugal.|d Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP) , Porto , Portugal.
authors.forename: Hugo
authors.initials: H
authors.lastname: Osório
authors.affiliation: a Instituto de Investigação e Inovação em Saúde, Universidade do Porto , Porto , Portugal.|b IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto , Porto , Portugal.|c ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Departamento de Biologia Molecular, Universidade do Porto , Porto , Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Moradas-Ferreira
authors.affiliation: a Instituto de Investigação e Inovação em Saúde, Universidade do Porto , Porto , Portugal.|b IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto , Porto , Portugal.|c ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Departamento de Biologia Molecular, Universidade do Porto , Porto , Portugal.
authors.forename: Vítor
authors.initials: V
authors.lastname: Costa
mesh_terms: D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D005947:Glucose / Q000378:metabolism; D006593:Hexokinase / Q000235:genetics* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D010101:Oxygen Consumption; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000172:deficiency / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D010750:Phosphoproteins; D029701:Saccharomyces cerevisiae Proteins; D006861:Hydrogen Peroxide; C490214:HXK2 protein, S cerevisiae; D006593:Hexokinase; D054648:Protein Phosphatase 2; C104343:SIT4 protein, S cerevisiae; D005947:Glucose
keywords: Ceramide; Hxk2p; Isc1p; Sit4p; cell cycle; chronological lifespan; oxidative stress