title: Mammalian SUN protein interaction networks at the inner nuclear membrane and their role in laminopathy disease processes.
abstract: The nuclear envelope (NE) LINC complex, in mammals comprised of SUN domain and nesprin proteins, provides a direct connection between the nuclear lamina and the cytoskeleton, which contributes to nuclear positioning and cellular rigidity. SUN1 and SUN2 interact with lamin A, but lamin A is only required for NE localization of SUN2, and it remains unclear how SUN1 is anchored. Here, we identify emerin and short nesprin-2 isoforms as novel nucleoplasmic binding partners of SUN1/2. These have overlapping binding sites distinct from the lamin A binding site. However, we demonstrate that tight association of SUN1 with the nuclear lamina depends upon a short motif within residues 209-228, a region that does not interact significantly with known SUN1 binding partners. Moreover, SUN1 localizes correctly in cells lacking emerin. Importantly then, the major determinant of SUN1 NE localization has yet to be identified. We further find that a subset of lamin A mutations, associated with laminopathies Emery-Dreifuss muscular dystrophy (EDMD) and Hutchinson-Gilford progeria syndrome (HGPS), disrupt lamin A interaction with SUN1 and SUN2. Despite this, NE localization of SUN1 and SUN2 is not impaired in cell lines from either class of patients. Intriguingly, SUN1 expression at the NE is instead enhanced in a significant proportion of HGPS but not EDMD cells and strongly correlates with pre-lamin A accumulation due to preferential interaction of SUN1 with pre-lamin A. We propose that these different perturbations in lamin A-SUN protein interactions may underlie the opposing effects of EDMD and HGPS mutations on nuclear and cellular mechanics.
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom.
authors.forename: Farhana
authors.initials: F
authors.lastname: Haque
authors.forename: Daniela
authors.initials: D
authors.lastname: Mazzeo
authors.forename: Jennifer T
authors.initials: JT
authors.lastname: Patel
authors.forename: Dawn T
authors.initials: DT
authors.lastname: Smallwood
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Ellis
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Shanahan
authors.forename: Sue
authors.initials: S
authors.lastname: Shackleton
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D034904:Lamin Type A / Q000737:chemistry; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism* / Q000502:physiology*; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000378:metabolism / Q000473:pathology*; D041681:NIH 3T3 Cells; D009685:Nuclear Envelope / Q000378:metabolism*; D009687:Nuclear Proteins / Q000502:physiology*; D011371:Progeria / Q000378:metabolism / Q000473:pathology*; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D034501:Telomere-Binding Proteins / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C506117:SUN1 protein, human; C464932:SUN1 protein, mouse; C413025:SUN2 protein, human; C520338:Sun2 protein, mouse; D034501:Telomere-Binding Proteins