title: ADF and Cofilin1 Control Actin Stress Fibers, Nuclear Integrity, and Cell Survival.
abstract: Genetic co-depletion of the actin-severing proteins ADF and CFL1 triggers catastrophic loss of adult homeostasis in multiple tissues. There is impaired cell-cell adhesion in skin keratinocytes with dysregulation of E-cadherin, hyperproliferation of differentiated cells, and ultimately apoptosis. Mechanistically, the primary consequence of depleting both ADF and CFL1 is uncontrolled accumulation of contractile actin stress fibers associated with enlarged focal adhesions at the plasma membrane, as well as reduced rates of membrane protrusions. This generates increased intracellular acto-myosin tension that promotes nuclear deformation and physical disruption of the nuclear lamina via the LINC complex that normally connects regulated actin filaments to the nuclear envelope. We therefore describe a pathway involving the actin-severing proteins ADF and CFL1 in regulating the dynamic turnover of contractile actin stress fibers, and this is vital to prevent the nucleus from being damaged by actin contractility, in turn preserving cell survival and tissue homeostasis.
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK.
authors.forename: Georgios
authors.initials: G
authors.lastname: Kanellos
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK.
authors.forename: Hitesh
authors.initials: H
authors.lastname: Patel
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Ridgway
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: David
authors.initials: D
authors.lastname: Huels
authors.affiliation: Institute of Genetics, University of Bonn, Karlrobert-Kreiten Strasse 13, 53115 Bonn, Germany.
authors.forename: Christine B
authors.initials: CB
authors.lastname: Gurniak
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Sandilands
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK.
authors.forename: Neil O
authors.initials: NO
authors.lastname: Carragher
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Institute of Genetics, University of Bonn, Karlrobert-Kreiten Strasse 13, 53115 Bonn, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Witke
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK.
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Brunton
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK. Electronic address: m.frame@ed.ac.uk.
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Frame
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D051378:Actin-Related Protein 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D051338:Cofilin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051345:Destrin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism; D000080865:Formins; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009252:NADPH Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: D051378:Actin-Related Protein 3; C495929:Actr3 protein, mouse; D015820:Cadherins; D002352:Carrier Proteins; C495811:Cfl1 protein, mouse; D051338:Cofilin 1; D051345:Destrin; C491464:Diap1 protein, mouse; C495825:Dstn protein, mouse; D000080865:Formins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C485903:Syne2 protein, mouse; C508552:Dia2 protein, mouse; D009252:NADPH Dehydrogenase