Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by Linking the Nuclear Envelope to the Actin and Microtubule Cytoskeleton

Dev Cell. 2015 Oct 26;35(2):186-98. doi: 10.1016/j.devcel.2015.09.018.

Abstract

Nucleus positioning is key for intracellular organization, cell differentiation, and organ development and is affected in many diseases, including myopathies due to alteration in amphiphysin-2 (BIN1). The actin and microtubule cytoskeletons are essential for nucleus positioning, but their crosstalk in this process is sparsely characterized. Here, we report that impairment of amphiphysin/BIN1 in Caenorhabditis elegans, mammalian cells, or muscles from patients with centronuclear myopathy alters nuclear position and shape. We show that AMPH-1/BIN1 binds to nesprin and actin, as well as to the microtubule-binding protein CLIP170 in both species. Expression of the microtubule-anchoring CAP-GLY domain of CLIP170 fused to the nuclear-envelope-anchoring KASH domain of nesprin rescues nuclear positioning defects of amph-1 mutants. Amphiphysins thus play a central role in linking the nuclear envelope with the actin and microtubule cytoskeletons. We propose that BIN1 has a direct and evolutionarily conserved role in nuclear positioning, altered in myopathies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Animals
  • COS Cells
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Cell Nucleus / genetics*
  • Cell Shape / genetics
  • Chlorocebus aethiops
  • Cytoplasm / metabolism
  • Cytoskeleton / genetics
  • Cytoskeleton / metabolism
  • Cytoskeleton / pathology
  • HEK293 Cells
  • Humans
  • Microfilament Proteins / genetics*
  • Microfilament Proteins / metabolism
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / metabolism
  • Microtubules / genetics
  • Microtubules / metabolism
  • Multiprotein Complexes
  • Muscle, Skeletal / metabolism
  • Myopathies, Structural, Congenital / genetics*
  • Myopathies, Structural, Congenital / metabolism
  • Myopathies, Structural, Congenital / pathology
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Nuclear Envelope / genetics*
  • Nuclear Envelope / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism

Substances

  • Actins
  • Microfilament Proteins
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • SYNE2 protein, human
  • amphiphysin
  • cytoplasmic linker protein 170