title: Prelamin A-mediated recruitment of SUN1 to the nuclear envelope directs nuclear positioning in human muscle.
abstract: Lamin A is a nuclear lamina constituent expressed in differentiated cells. Mutations in the LMNA gene cause several diseases, including muscular dystrophy and cardiomyopathy. Among the nuclear envelope partners of lamin A are Sad1 and UNC84 domain-containing protein 1 (SUN1) and Sad1 and UNC84 domain-containing protein 2 (SUN2), which mediate nucleo-cytoskeleton interactions critical to the anchorage of nuclei. In this study, we show that differentiating human myoblasts accumulate farnesylated prelamin A, which elicits upregulation and recruitment of SUN1 to the nuclear envelope and favors SUN2 enrichment at the nuclear poles. Indeed, impairment of prelamin A farnesylation alters SUN1 recruitment and SUN2 localization. Moreover, nuclear positioning in myotubes is severely affected in the absence of farnesylated prelamin A. Importantly, reduced prelamin A and SUN1 levels are observed in Emery-Dreifuss muscular dystrophy (EDMD) myoblasts, concomitant with altered myonuclear positioning. These results demonstrate that the interplay between SUN1 and farnesylated prelamin A contributes to nuclear positioning in human myofibers and may be implicated in pathogenetic mechanisms.
authors.affiliation: Institute for Molecular Genetics, IGM-CNR, Unit of Bologna, Bologna, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Mattioli
authors.forename: M
authors.initials: M
authors.lastname: Columbaro
authors.forename: C
authors.initials: C
authors.lastname: Capanni
authors.forename: N M
authors.initials: NM
authors.lastname: Maraldi
authors.forename: V
authors.initials: V
authors.lastname: Cenni
authors.forename: K
authors.initials: K
authors.lastname: Scotlandi
authors.forename: M T
authors.initials: MT
authors.lastname: Marino
authors.forename: L
authors.initials: L
authors.lastname: Merlini
authors.forename: S
authors.initials: S
authors.lastname: Squarzoni
authors.forename: G
authors.initials: G
authors.lastname: Lattanzi
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D034904:Lamin Type A; D008148:Lovastatin / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D009685:Nuclear Envelope / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D054876:Prenylation; D011498:Protein Precursors / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
chemical_list: D000924:Anticholesteremic Agents; D047908:Intracellular Signaling Peptides and Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C506117:SUN1 protein, human; C413025:SUN2 protein, human; C090764:prelamin A; D008148:Lovastatin