title: Dysferlin-mediated phosphatidylserine sorting engages macrophages in sarcolemma repair.
abstract: Failure to repair the sarcolemma leads to muscle cell death, depletion of stem cells and myopathy. Hence, membrane lesions are instantly sealed by a repair patch consisting of lipids and proteins. It has remained elusive how this patch is removed to restore cell membrane integrity. Here we examine sarcolemmal repair in live zebrafish embryos by real-time imaging. Macrophages remove the patch. Phosphatidylserine (PS), an 'eat-me' signal for macrophages, is rapidly sorted from adjacent sarcolemma to the repair patch in a Dysferlin (Dysf) dependent process in zebrafish and human cells. A previously unrecognized arginine-rich motif in Dysf is crucial for PS accumulation. It carries mutations in patients presenting with limb-girdle muscular dystrophy 2B. This underscores the relevance of this sequence and uncovers a novel pathophysiological mechanism underlying this class of myopathies. Our data show that membrane repair is a multi-tiered process involving immediate, cell-intrinsic mechanisms as well as myofiber/macrophage interactions.
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Middel
authors.affiliation: Institute of Applied Physics, Karlsruhe Institute of Technology (KIT), Wolfgang-Gaede-Straße 1, 76131 Karlsruhe, Germany.|Institute of Nanotechnology, Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Masanari
authors.initials: M
authors.lastname: Takamiya
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Beil
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Maryam
authors.initials: M
authors.lastname: Shahid
authors.affiliation: Institute of Inflammation and Repair, The University of Manchester, Oxford Road, Manchester M13 9PL, UK.
authors.forename: Urmas
authors.identifier: 0000-0002-7849-2055
authors.initials: U
authors.lastname: Roostalu
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Grabher
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Sepand
authors.initials: S
authors.lastname: Rastegar
authors.affiliation: Institute for Applied Computer Science, Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Reischl
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.|Institute of Applied Physics, Karlsruhe Institute of Technology (KIT), Wolfgang-Gaede-Straße 1, 76131 Karlsruhe, Germany.|Institute of Nanotechnology, Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.|Department of Physics, University of Illinois at Urbana-Champaign, 1110 West Green Street, 61801 Urbana, Illinois, US.
authors.forename: Gerd Ulrich
authors.identifier: 0000-0002-5027-3192
authors.initials: GU
authors.lastname: Nienhaus
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), PO Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Strähle
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001120:Arginine / Q000235:genetics; D000073939:Dysferlin / Q000235:genetics / Q000378:metabolism*; D004625:Embryo, Nonmammalian; D006367:HeLa Cells; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics*; D010718:Phosphatidylserines / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D010718:Phosphatidylserines; D029961:Zebrafish Proteins; C568333:dysf protein, zebrafish; D001120:Arginine