title: Identification of new surfaces of cofilin that link mitochondrial function to the control of multi-drug resistance.
abstract: ADF/cofilin family proteins are essential regulators of actin cytoskeletal dynamics. Recent evidence also implicates cofilin in the regulation of mitochondrial function. Here, we identify new functional surfaces of cofilin that are linked with mitochondrial function and stress responses in the budding yeast Saccharomyces cerevisiae. Our data link surfaces of cofilin that are involved in separable activities of actin filament disassembly or stabilisation, to the regulation of mitochondrial morphology and the activation status of Ras, respectively. Importantly, charge alterations to conserved surfaces of cofilin that do not interfere with its actin regulatory activity lead to a dramatic increase in respiratory function that triggers a retrograde signal to upregulate a battery of ABC transporters and concurrent metabolic changes that support multi-drug resistance. We hypothesise that cofilin functions within a bio-sensing system that connects the cytoskeleton and mitochondrial function to environmental challenge.
authors.affiliation: Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent, UK.
authors.forename: Vassilios N
authors.initials: VN
authors.lastname: Kotiadis
authors.forename: Jane E
authors.initials: JE
authors.lastname: Leadsham
authors.forename: Emma L
authors.initials: EL
authors.lastname: Bastow
authors.forename: Aline
authors.initials: A
authors.lastname: Gheeraert
authors.forename: Jennafer M
authors.initials: JM
authors.lastname: Whybrew
authors.forename: Martin
authors.initials: M
authors.lastname: Bard
authors.forename: Pekka
authors.initials: P
authors.lastname: Lappalainen
authors.forename: Campbell W
authors.initials: CW
authors.lastname: Gourlay
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D051339:Actin Depolymerizing Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000199:Actins / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000666:Amphotericin B / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology; D001665:Binding Sites; D018432:Drug Resistance, Multiple / Q000187:drug effects; D015966:Gene Expression Regulation, Fungal; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D055672:Static Electricity; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D051339:Actin Depolymerizing Factors; D000199:Actins; D001393:Azoles; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D000666:Amphotericin B; D018631:ras Proteins