A dynamic actin cytoskeleton is required to prevent constitutive VDAC-dependent MAPK signalling and aberrant lipid homeostasis
Jack Davis,
Thorsten Meyer,
Martin Smolnig,
Daniel G.J. Smethurst,
Lisa Neuhaus,
Jonas Heyden,
Filomena Broeskamp,
Elizabeth S.M. Edrich,
Oskar Knittelfelder,
Dagmar Kolb,
Tobias von der Haar,
Campbell W. Gourlay,
Patrick Rockenfeller
Affiliations
Jack Davis
Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent, UK
Thorsten Meyer
Chair of Biochemistry and Molecular Medicine, Center for Biomedical Education and Research (ZBAF), University of Witten/Herdecke (UW/H), Stockumer Str. 10, 58453 Witten, Germany
Martin Smolnig
Chair of Biochemistry and Molecular Medicine, Center for Biomedical Education and Research (ZBAF), University of Witten/Herdecke (UW/H), Stockumer Str. 10, 58453 Witten, Germany
Daniel G.J. Smethurst
Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent, UK
Lisa Neuhaus
Chair of Biochemistry and Molecular Medicine, Center for Biomedical Education and Research (ZBAF), University of Witten/Herdecke (UW/H), Stockumer Str. 10, 58453 Witten, Germany
Jonas Heyden
Chair of Biochemistry and Molecular Medicine, Center for Biomedical Education and Research (ZBAF), University of Witten/Herdecke (UW/H), Stockumer Str. 10, 58453 Witten, Germany
Filomena Broeskamp
Chair of Biochemistry and Molecular Medicine, Center for Biomedical Education and Research (ZBAF), University of Witten/Herdecke (UW/H), Stockumer Str. 10, 58453 Witten, Germany
Elizabeth S.M. Edrich
Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent, UK
Oskar Knittelfelder
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
Dagmar Kolb
Medical University of Graz, Core Facility Ultrastructure Analysis, Neue Stiftingtalstraße 6/II, 8010 Graz, Austria; Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, Neue Stiftingtalstraße 6/II, 8010 Graz, Austria
Tobias von der Haar
Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent, UK
Campbell W. Gourlay
Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent, UK; Corresponding author
Patrick Rockenfeller
Chair of Biochemistry and Molecular Medicine, Center for Biomedical Education and Research (ZBAF), University of Witten/Herdecke (UW/H), Stockumer Str. 10, 58453 Witten, Germany; Corresponding author
Summary: The dynamic nature of the actin cytoskeleton is required to coordinate many cellular processes, and a loss of its plasticity has been linked to accelerated cell aging and attenuation of adaptive response mechanisms. Cofilin is an actin-binding protein that controls actin dynamics and has been linked to mitochondrial signaling pathways that control drug resistance and cell death. Here we show that cofilin-driven chronic depolarization of the actin cytoskeleton activates cell wall integrity mitogen-activated protein kinase (MAPK) signalling and disrupts lipid homeostasis in a voltage-dependent anion channel (VDAC)-dependent manner. Expression of the cof1-5 mutation, which reduces the dynamic nature of actin, triggers loss of cell wall integrity, vacuole fragmentation, disruption of lipid homeostasis, lipid droplet (LD) accumulation, and the promotion of cell death. The integrity of the actin cytoskeleton is therefore essential to maintain the fidelity of MAPK signaling, lipid homeostasis, and cell health in S. cerevisiae.
