Journal
CURRENT BIOLOGY
Volume 27, Issue 19, Pages 2999-+Publisher
CELL PRESS
DOI: 10.1016/j.cub.2017.08.031
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Funding
- International Research Training Group in Myology-MyoGrad [DFG GK1631]
- French-German University (UFA-DFH) [CT-46-14-II]
- Fondation pour la Recherche Medicale (FRM) [FDT20160435051]
- Agence Nationale pour la Recherche [ANR-14-CE09-0006-04]
- Association Institut de Myologie
- Merlion Project [6.06.14]
- Singapore Agency for Science, Technology and Research (A*STAR) Biomedical Research Council (BMRC) [SPF2012/005]
- European Research Council [617676]
- FEDER through POR Lisboa Pro-grama Operacional Regional de Lisboa, PORTUGAL [LISBOA-01-0145-FEDER-007391]
- Fundacao para a Ciencia e a Tecnologia
- European Molecular Biology Organization
- German Research Foundation (DFG) [SFB958/Z02]
- European Research Council (ERC) [617676] Funding Source: European Research Council (ERC)
- Agence Nationale de la Recherche (ANR) [ANR-14-CE09-0006] Funding Source: Agence Nationale de la Recherche (ANR)
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The nucleus is the main microtubule-organizing center (MTOC) in muscle cells due to the accumulation of centrosomal proteins and microtubule (MT) nucleation activity at the nuclear envelope (NE) [1-4]. The relocalization of centrosomal proteins, including Pericentrin, Pcm1, and gamma-tubulin, depends on Nesprin-1, an outer nuclear membrane (ONM) protein that connects the nucleus to the cytoskeleton via its N-terminal region [5-7]. Nesprins are also involved in the recruitment of kinesin to the NE and play a role in nuclear positioning in skeletal muscle cells [8-12]. However, a function for MT nucleation from the NE in nuclear positioning has not been established. Using the proximity-dependent biotin identification (BioID) method [13, 14], we found several centrosomal proteins, including Akap450, Pcm1, and Pericentrin, whose association with Nesprin-1 alpha is increased in differentiated myotubes. We show that Nesprin-1 alpha recruits Akap450 to the NE independently of kinesin and that Akap450, but not other centrosomal proteins, is required for MT nucleation from the NE. Furthermore, we demonstrate that this mechanism is disrupted in congenital muscular dystrophy patient myotubes carrying a nonsense mutation within the SYNE1 gene (23560 G>T) encoding Nesprin-1 [15, 16]. Finally, using computer simulation and cell culture systems, we provide evidence for a role of MT nucleation from the NE on nuclear spreading in myotubes. Our data thus reveal a novel function for Nesprin-1 alpha/Nesprin-1 in nuclear positioning through recruitment of Akap450-mediated MT nucleation activity to the NE.
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