PUBLICATION

Dysferlin-mediated phosphatidylserine sorting engages macrophages in sarcolemma repair

Authors
Middel, V., Zhou, L., Takamiya, M., Beil, T., Shahid, M., Roostalu, U., Grabher, C., Rastegar, S., Reischl, M., Nienhaus, G.U., Strähle, U.
ID
ZDB-PUB-160920-6
Date
2016
Source
Nature communications   7: 12875 (Journal)
Registered Authors
Beil, Tanja, Grabher, Clemens, Middel, Volker, Rastegar, Sepand, Roostalu, Urmas, Shahid, Maryam, Strähle, Uwe, Takamiya, Masanari
Keywords
Imaging the immune system, Mechanisms of disease, Membrane trafficking
MeSH Terms
  • Dysferlin/genetics
  • Dysferlin/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Arginine/genetics
  • Sarcolemma/metabolism*
  • Muscular Dystrophies, Limb-Girdle/genetics*
  • Embryo, Nonmammalian
  • Humans
  • Animals
  • Phosphatidylserines/metabolism*
  • HeLa Cells
  • Animals, Genetically Modified
  • Macrophages/physiology*
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism*
  • Zebrafish
(all 17)
PubMed
27641898 Full text @ Nat. Commun.
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.
Genes / Markers
Figures
Figure Gallery (9 images)
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Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
EGFPgl22Tglight damage: sarcolemma: muscle cellProtruding-mouth to Day 5IFL
1 - 1 of 1
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Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
gl22TgTransgenic Insertion
    ka86
      Small Deletion
      ka87
        Unknown
        ka88
          Unknown
          ka89
            Unknown
            ka90
              Unknown
              nz50TgTransgenic Insertion
                1 - 7 of 7
                Show
                Human Disease / Model
                No data available
                Sequence Targeting Reagents
                Target Reagent Reagent Type
                anxa6MO1-anxa6MRPHLNO
                csf3rMO3-csf3rMRPHLNO
                dysfCRISPR1-dysfCRISPR
                dysfMO5-dysfMRPHLNO
                irf8CRISPR1-irf8CRISPR
                irf8MO1-irf8MRPHLNO
                spi1bMO1-spi1bMRPHLNO
                1 - 7 of 7
                Show
                Fish
                Antibodies
                No data available
                Orthology
                No data available
                Engineered Foreign Genes
                Marker Marker Type Name
                DsRed2EFGDsRed2
                EGFPEFGEGFP
                1 - 2 of 2
                Show
                Mapping
                No data available