Nesprin interchain associations control nuclear size.
Nesprins-1/-2/-3/-4 are nuclear envelope proteins, which connect nuclei to the cytoskeleton. The largest nesprin-1/-2 isoforms (termed giant)  tether F-actin through their N-terminal actin binding domain (ABD). Nesprin-3, however, lacks an ABD and associates instead to plectin, which binds intermediate filaments. Nesprins are integrated into the outer nuclear membrane via their C-terminal KASH-domain. Here, we show that nesprin-1/-2 ABDs physically and functionally interact with nesprin-3. Thus, both ends of nesprin-1/-2 giant are integrated at the nuclear surface: via the C-terminal KASH-domain and the N-terminal ABD-nesprin-3 association. Interestingly, nesprin-2 ABD or KASH-domain overexpression leads to increased nuclear areas. Conversely, nesprin-2 mini (contains the ABD and KASH-domain but lacks the massive nesprin-2 giant rod segment) expression yields smaller nuclei. Nuclear shrinkage is further enhanced upon nesprin-3 co-expression or microfilament depolymerization. Our findings suggest that multivariate intermolecular nesprin interactions with the cytoskeleton form a lattice-like filamentous network covering the outer nuclear membrane, which determines nuclear size.
School of Biological and Biomedical Sciences, University of Durham, Durham, UK.
Wenshu
W
Lu
Maria
M
Schneider
Sascha
S
Neumann
Verena-Maren
VM
Jaeger
Surayya
S
Taranum
Martina
M
Munck
Sarah
S
Cartwright
Christine
C
Richardson
James
J
Carthew
Kowoon
K
Noh
Martin
M
Goldberg
Angelika A
AA
Noegel
Iakowos
I
Karakesisoglou
D000199:Actins / Q000378:metabolism*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005799:Genes, Dominant; D006801:Humans; D047468:Immunoprecipitation; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics
D000199:Actins; D003598:Cytoskeletal Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C415465:SYNE1 protein, human; C485904:SYNE2 protein, human; C529565:SYNE3 protein, human