Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by Linking the Nuclear Envelope to the Actin and Microtubule Cytoskeleton.
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.
IGBMC, INSERM U964, CNRS UMR7104, Strasbourg University, 67404 Illkirch, France; University Claude Bernard Lyon 1, CGphiMC UMR CNRS 5534, 69622 Villeurbanne, France. Electronic address: manuela.dalessandro2@gmail.com.
Manuela
M
D'Alessandro
IGBMC, INSERM U964, CNRS UMR7104, Strasbourg University, 67404 Illkirch, France.
Karim
K
Hnia
Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris 6, 75634 Paris, France; CNRS UMR5239, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Ecole Normale Supérieure de Lyon, 69364 Lyon Cedex 07, France.
Vincent
V
Gache
IGBMC, INSERM U964, CNRS UMR7104, Strasbourg University, 67404 Illkirch, France.
Catherine
C
Koch
IGBMC, INSERM U964, CNRS UMR7104, Strasbourg University, 67404 Illkirch, France.
Christos
C
Gavriilidis
IGBMC, INSERM U964, CNRS UMR7104, Strasbourg University, 67404 Illkirch, France.
David
D
Rodriguez
IGBMC, INSERM U964, CNRS UMR7104, Strasbourg University, 67404 Illkirch, France.
Anne-Sophie
AS
Nicot
Morphology Neuromuscular Unit of the Myology Institute, GHU Pitié-Salpêtrière, 75013 Paris, France.
Norma B
NB
Romero
IGBMC, INSERM U964, CNRS UMR7104, Strasbourg University, 67404 Illkirch, France; Cell Biology and Biophysics Unit, EMBL Heidelberg, 69117 Heidelberg, Germany.
Yannick
Y
Schwab
Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris 6, 75634 Paris, France; Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal.
Edgar
E
Gomes
IGBMC, INSERM U964, CNRS UMR7104, Strasbourg University, 67404 Illkirch, France; UMR7622, IBPS, UPMC, 75252 Paris, France.
Michel
M
Labouesse
IGBMC, INSERM U964, CNRS UMR7104, Strasbourg University, 67404 Illkirch, France. Electronic address: jocelyn@igbmc.fr.
Jocelyn
J
Laporte
D000199:Actins / Q000235:genetics; D000818:Animals; D019556:COS Cells; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics*; D048430:Cell Shape / Q000235:genetics; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes; D018482:Muscle, Skeletal / Q000378:metabolism; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009685:Nuclear Envelope / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism
D000199:Actins; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C485904:SYNE2 protein, human; C075637:amphiphysin; C076744:cytoplasmic linker protein 170