title: The cytolinker plectin regulates nuclear mechanotransduction in keratinocytes.
abstract: The transmission of mechanical forces to the nucleus is important for intracellular positioning, mitosis and cell motility, yet the contribution of specific components of the cytoskeleton to nuclear mechanotransduction remains unclear. In this study, we examine how crosstalk between the cytolinker plectin and F-actin controls keratin network organisation and the 3D nuclear morphology of keratinocytes. Using micro-patterned surfaces to precisely manipulate cell shape, we find that cell adhesion and spreading regulate the size and shape of the nucleus. Disruption of the keratin cytoskeleton through loss of plectin facilitated greater nuclear deformation, which depended on acto-myosin contractility. Nuclear morphology did not depend on direct linkage of the keratin cytoskeleton with the nuclear membrane, rather loss of plectin reduced keratin filament density around the nucleus. We further demonstrate that keratinocytes have abnormal nuclear morphologies in the epidermis of plectin-deficient, epidermolysis bullosa simplex patients. Taken together, our data demonstrate that plectin is an essential regulator of nuclear morphology in vitro and in vivo and protects the nucleus from mechanical deformation.
authors.affiliation: School of Engineering and Materials Science, Queen Mary, University of London, London, E1 4NS UK Centre for Cell Biology and Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, E1 2AT UK.
authors.forename: Filipe V
authors.initials: FV
authors.lastname: Almeida
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, London, SE1 9RT UK.
authors.forename: Gernot
authors.initials: G
authors.lastname: Walko
authors.affiliation: The National Diagnostic EB Laboratory, Viapath, St Thomas' Hospital, London, SE1 7EH UK.
authors.forename: James R
authors.initials: JR
authors.lastname: McMillan
authors.affiliation: St John's Institute of Dermatology, King's College London (Guy's Campus), London, SE1 9RT UK.
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.affiliation: Max F. Perutz Laboratories, Department of Biochemistry and Cell Biology, University of Vienna, 1030 Vienna, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wiche
authors.affiliation: School of Engineering and Materials Science, Queen Mary, University of London, London, E1 4NS UK.
authors.forename: Asa H
authors.initials: AH
authors.lastname: Barber
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, E1 2AT UK j.connelly@qmul.ac.uk.
authors.forename: John T
authors.initials: JT
authors.lastname: Connelly
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D051190:Plectin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495332:PLEC protein, human; C495333:Plec protein, mouse; D051190:Plectin
keywords: Cyoskeleton; Keratin; Keratinocyte; Mechanics; Nucleus; Plectin