ZFIN ID: ZDB-PUB-160920-6
Dysferlin-mediated phosphatidylserine sorting engages macrophages in sarcolemma repair
Middel, V., Zhou, L., Takamiya, M., Beil, T., Shahid, M., Roostalu, U., Grabher, C., Rastegar, S., Reischl, M., Nienhaus, G.U., Strähle, U.
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:
  • Animals
  • Animals, Genetically Modified
  • Arginine/genetics
  • Dysferlin/genetics
  • Dysferlin/metabolism*
  • Embryo, Nonmammalian
  • HeLa Cells
  • Humans
  • Macrophages/physiology*
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism*
  • Muscular Dystrophies, Limb-Girdle/genetics*
  • Phosphatidylserines/metabolism*
  • Sarcolemma/metabolism*
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 27641898 Full text @ Nat. Commun.
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.