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

• Published in: Developmental cell 2015-10, Vol.35 (2), p.186-198
• Main Authors: D’Alessandro, Manuela, Hnia, Karim, Gache, Vincent, Koch, Catherine, Gavriilidis, Christos, Rodriguez, David, Nicot, Anne-Sophie, Romero, Norma B., Schwab, Yannick, Gomes, Edgar, Labouesse, Michel, Laporte, Jocelyn
• Format: Article
• Language: English
• Subjects: Actins - genetics; Animals; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Cell Nucleus - genetics; Cell Shape - genetics; Cercopithecus aethiops; COS Cells; Cytoplasm - metabolism; Cytoskeleton - genetics; Cytoskeleton - metabolism; Cytoskeleton - pathology; Development Biology; HEK293 Cells; Humans; Life Sciences; 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
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2015.09.018

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. [Display omitted] •Amphiphysin/BIN1 has an evolutionarily conserved role in nuclear positioning•Amphiphysin interacts with the nuclear envelope protein nesprin•Amphiphysin binds both actin and the microtubule plus-end-binding protein CLIP170•Amphiphysin mutations causing myopathy impair nuclear position and shape Organelle positioning defects are seen in many human diseases. D’Alessandro et al. show that amphiphysin (BIN1) controls nuclear positioning and shape. BIN1 acts by linking microtubule plus-end-binding protein CLIP170 or actin with nuclear envelope protein nesprin in a conserved mechanism that is impaired in myopathies with BIN1 mutations.