Linear Arrays of Nuclear Envelope Proteins Harness Retrograde Actin Flow for Nuclear Movement

Luxton, G. W. Gant; Gomes, Edgar R.; Folker, Eric S.; Vintinner, Erin; Gundersen, Gregg G.

doi:10.1126/science.1189072

Cited by 417 publications

(605 citation statements)

References 26 publications

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“…In addition, given recent interests on molecular linkages between apical actin filaments and nuclear membrane 18,19 , it will be interesting to investigate whether such links exist for central actin filaments and influence the force transmission process.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, Khatau et al 18 have reported the presence of a dome-like actin structure, called the actin cap, that covers the top of the nucleus, and their results suggest that this structure is involved in a part of the nuclear shape deformation. More recently, a physical connection between an array of actin filaments located above the nucleus and the nuclear membrane, called transmembrane actin-associated nuclear lines, have been observed to be implicated in the intracellular localization of the nucleus 19 . Furthermore, perturbations of the intermediate filament network could alter the positioning of the nucleus in both migrating and immobile astrocytes, suggesting that cytoplasmic intermediate filaments are involved in actin-dependent positioning of the nucleus 20 .…”

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confidence: 99%

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Spatial coordination between cell and nuclear shape within micropatterned endothelial cells

2012

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Growing evidence suggests that cytoplasmic actin filaments are essential factors in the modulation of nuclear shape and function. However, the mechanistic understanding of the internal orchestration between cell and nuclear shape is still lacking. Here we show that orientation and deformation of the nucleus are regulated by lateral compressive forces driven by tension in central actomyosin fibres. By using a combination of micro-manipulation tools, our study reveals that tension in central stress fibres is gradually generated by anisotropic force contraction dipoles, which expand as the cell elongates and spreads. our findings indicate that large-scale cell shape changes induce a drastic condensation of chromatin and dramatically affect cell proliferation. on the basis of these findings, we propose a simple mechanical model that quantitatively accounts for our experimental data and provides a conceptual framework for the mechanistic coordination between cell and nuclear shape.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Spatial coordination between cell and nuclear shape within micropatterned endothelial cells

2012

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“…In the lumen of the NE, the SUN domain interacts with the KASH domain, ensuring that KASH domain proteins are targeted to the ONM. During actin-dependent nuclear movement, the LINC complex components Nesprin 2G and SUN2 were found to provide a direct linkage between the nucleus and the actin network [18,19]. Recently, mutations of KASH domain proteins have been linked to Emery-Dreifuss muscular dystrophy [20,21].…”

Section: Introductionmentioning

confidence: 99%

Structural insights into SUN-KASH complexes across the nuclear envelope

et al. 2012

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Linker of the nucleoskeleton and the cytoskeleton (LINC) complexes are composed of SUN and KASH domaincontaining proteins and bridge the inner and outer membranes of the nuclear envelope. LINC complexes play critical roles in nuclear positioning, cell polarization and cellular stiffness. Previously, we reported the homotrimeric structure of human SUN2. We have now determined the crystal structure of the human SUN2-KASH complex. In the complex structure, the SUN domain homotrimer binds to three independent "hook"-like KASH peptides. The overall conformation of the SUN domain in the complex closely resembles the SUN domain in its apo state. A major conformational change involves the AA'-loop of KASH-bound SUN domain, which rearranges to form a mini β-sheet that interacts with the KASH peptide. The PPPT motif of the KASH domain fits tightly into a hydrophobic pocket on the homotrimeric interface of the SUN domain, which we termed the BI-pocket. Moreover, two adjacent protomers of the SUN domain homotrimer sandwich the KASH domain by hydrophobic interaction and hydrogen bonding. Mutations of these binding sites disrupt or reduce the association between the SUN and KASH domains in vitro. In addition, transfection of wild-type, but not mutant, SUN2 promotes cell migration in Ovcar-3 cells. These results provide a structural model of the LINC complex, which is essential for additional study of the physical and functional coupling between the cytoplasm and the nucleoplasm.

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“…Nesprins interact with cytoskeletal elements, and both nesprins and SUNs contribute to nuclear movement and positioning during development and in migrating cells (10)(11)(12)(13). Recent work has shown that multiple LINC complexes assemble into transmembrane actin-associated nuclear (TAN) lines that attach nuclei to actin filaments during nuclear movement as fibroblasts polarize to migrate (13).…”

mentioning

confidence: 99%

“…Interactions between the nucleus and cytoskeleton are mediated by the linker of nucleoskeleton and cytoskeleton (LINC) complex, which spans the nuclear envelope via nesprin proteins in the outer nuclear membrane and SUN proteins in the inner nuclear membrane (9). Nesprins interact with cytoskeletal elements, and both nesprins and SUNs contribute to nuclear movement and positioning during development and in migrating cells (10)(11)(12)(13). Recent work has shown that multiple LINC complexes assemble into transmembrane actin-associated nuclear (TAN) lines that attach nuclei to actin filaments during nuclear movement as fibroblasts polarize to migrate (13).…”

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confidence: 99%

Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement

Folker

Östlund

Luxton

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in LMNA, which encodes A-type lamins, result in disparate diseases, known collectively as laminopathies, that affect distinct tissues, including striated muscle and adipose tissue. Lamins provide structural support for the nucleus and sites of attachment for chromatin, and defects in these functions may contribute to disease pathogenesis. Recent studies suggest that A-type lamins may facilitate connections between the nucleus and the cytoskeleton mediated by nuclear envelope nesprin and SUN proteins. In mammalian cells, however, interfering with A-type lamins does not affect the localization of these proteins. Here, we used centrosome orientation in fibroblasts, which requires separate nuclear and centrosome positioning pathways, as a model system to understand how LMNA mutations affect nucleus-cytoskeletal connections. We find that LMNA mutations causing striated muscle diseases block actin-dependent nuclear movement, whereas most that affect adipose tissue inhibit microtubule-dependent centrosome positioning. Genetic deletion or transient depletion of A-type lamins also blocked nuclear movement, showing that mutations affecting muscle exhibit the null phenotype. Lack of A-type lamins, or expression of variants that cause striated muscle disease, did not affect assembly of nesprin-2G and SUN2 into transmembrane actinassociated nuclear (TAN) lines that attach the nucleus to retrogradely moving actin cables. Nesprin-2G TAN lines were less stable, however, and slipped over the nucleus rather than moving with it, indicating that they were not anchored. Nesprin-2G TAN lines also slipped in SUN2-depleted cells. Our results establish A-type lamins as anchors for nesprin-2G-SUN2 TAN lines to allow productive movement and proper positioning of the nucleus by actin.nesprin SUN | linker of nucleoskeleton and cytoskeleton complex | muscular dystrophy L amin A and lamin C, the predominant A-type lamins, are expressed in most differentiated somatic cells. Yet, different mutations in the LMNA gene encoding these proteins result in a variety of diseases that affect specific tissues. LMNA mutations cause autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) and related diseases with dilated cardiomyopathy (DCM) that affect cardiac muscle and skeletal muscle to variable degrees (1). Other LMNA mutations cause Dunnigan-type familial partial lipodystrophy (FPLD) that affects adipose tissue (2), Charcot-Marie-Tooth type 2B1 disease that affects peripheral neurons (3), and progeroid syndromes with features of accelerated aging (4, 5). The mechanism whereby mutations in a single gene that is widely expressed cause such diverse diseases remains a puzzle.There are two prevailing hypotheses to explain the pathogenesis of laminopathies. The mechanical stress hypothesis proposes that alterations in A-type lamins compromise nuclear integrity in tissues susceptible to stress, such as striated muscle. This model is supported by findings that A-type lamin deficiency disrupts nuclear integrity in model systems (6, 7). The secon...

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Linear Arrays of Nuclear Envelope Proteins Harness Retrograde Actin Flow for Nuclear Movement

Cited by 417 publications

References 26 publications

Spatial coordination between cell and nuclear shape within micropatterned endothelial cells

Spatial coordination between cell and nuclear shape within micropatterned endothelial cells

Structural insights into SUN-KASH complexes across the nuclear envelope

Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement

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