Lamin A/C–dependent Localization of Nesprin-2, a Giant Scaffolder at the Nuclear Envelope

Libotte, Thorsten; Zaim, Hafida; Abraham, Sabu; Padmakumar, V. C.; Schneider, Maria; Lu, Wenshu; Munck, Martina; Hutchison, Christopher J.; Wehnert, Manfred; Fahrenkrog, Birthe; Sauder, Ursula; Aebi, Ueli; Noegel, Angelika A.; Karakesisoglou, Iakowos

doi:10.1091/mbc.e04-11-1009

Cited by 155 publications

(195 citation statements)

References 38 publications

Supporting

Mentioning

180

Contrasting

Unclassified

Order By: Relevance

“…This anchoring function of lamin A/C is distinct from that involved in localizing some inner nuclear membrane proteins, because, for example, SUN2 localization is not altered in lamin A/C-deficient cells (19,34). Also, whereas nesprin-2G levels are somewhat reduced in lamin A/C-deficient cells, increasing nesprin-2G levels did not rescue nuclear movement, showing that lamin A/C plays a role beyond simply localizing nesprin-2G to the nucleus.…”

Section: Discussionmentioning

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.

166

202

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

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.

166

202

View full text Add to dashboard Cite

show abstract

“…Minor defects in the nuclear envelope, including mutations in lamin and emerin, lead to a variety of human diseases termed laminopathies (reviewed in Mounkes et al, 2003). Furthermore, the Syne-1 and Syne-2 KASH domain proteins have been found to interact with emerin and lamin (Mislow et al, 2002;Libotte et al, 2005;Zhang et al, 2005). Likewise, SUN proteins Sun1 and Sun2 interact with lamin (Hodzic et al, 2004;Padmakumar et al, 2005).…”

Section: Conservation and Roles Of Sun-kash Protein Interactionsmentioning

confidence: 99%

UNC-83 Is a KASH Protein Required for Nuclear Migration and Is Recruited to the Outer Nuclear Membrane by a Physical Interaction with the SUN Protein UNC-84

McGee

Rillo

Anderson

et al. 2006

MBoC

127

180

View full text Add to dashboard Cite

UNC-84 is required to localize UNC-83 to the nuclear envelope where it functions during nuclear migration. A KASH domain in UNC-83 was identified. KASH domains are conserved in the nuclear envelope proteins Syne/nesprins, Klarsicht, MSP-300, and ANC-1. Caenorhabditis elegans UNC-83 was shown to localize to the outer nuclear membrane and UNC-84 to the inner nuclear membrane in transfected mammalian cells, suggesting the KASH and SUN protein targeting mechanisms are conserved. Deletion of the KASH domain of UNC-83 blocked nuclear migration and localization to the C. elegans nuclear envelope. Some point mutations in the UNC-83 KASH domain disrupted nuclear migration, even if they localized normally. At least two separable portions of the C-terminal half of UNC-84 were found to interact with the UNC-83 KASH domain in a membrane-bound, split-ubiquitin yeast two-hybrid system. However, the SUN domain was essential for UNC-84 function and UNC-83 localization in vivo. These data support the model that KASH and SUN proteins bridge the nuclear envelope, connecting the nuclear lamina to cytoskeletal components. This mechanism seems conserved across eukaryotes and is the first proposed mechanism to target proteins specifically to the outer nuclear membrane. INTRODUCTIONA variety of cellular and developmental processes, including fertilization, cell division, cell migration, and establishment of polarity, depend on positioning the nucleus to a specific location within the cell. For example, in budding yeast the nucleus must migrate to the bud neck before the onset of mitosis. Also, nuclei actively follow the leading edge of migratory cells, such as those in the developing cerebral cortex. Nuclear migration defects in these two examples lead to the missegregation of chromosomes or the neurological disease lissencephaly, respectively (reviewed in Morris, 2000). The role of microtubules and associated dynein and kinesin motors in nuclear migration are well established (reviewed in Reinsch and Gonczy, 1998). Although less established, actin also plays an important role in many nuclear positioning events (reviewed in Starr and Han, 2003). Recently, a definitive role for actin networks has been described in nuclear migration during NIH 3T3 cell polarization (Gomes et al., 2005). It remains relatively unknown how the nucleus connects to the cytoplasmic cytoskeleton during nuclear migration. Furthermore, it is not clear how the forces involved in nuclear positioning are transferred across both membranes of the nuclear envelope from the cytoskeleton to the nuclear matrix.We have previously proposed that two C. elegans proteins, UNC-84 and UNC-83, function to control nuclear migration by bridging the nuclear envelope, connecting the cytoskeleton with the nuclear matrix (Starr et al., 2001;Lee et al., 2002;Starr and Han, 2003). Mutations in unc-83 or unc-84 disrupt nuclear migration in at least three cell types: embryonic hypodermal hyp7 precursors, larval hypodermal P-cells, and embryonic intestinal primordial cells (Horvitz and Sulst...

show abstract

“…As well, nuclei shape from these fibroblasts is only mildly altered and the mice do not exhibit any symptoms of muscle diseases. Furthermore, lamin C has also been shown to be sufficient for proper localization of both emerin [14] and nesprin-2 [15] at the nuclear envelope. These studies therefore suggest that lamin C can substitute for lamin A on its own and provide functional support to the nuclear envelope.…”

Section: Introductionmentioning

confidence: 99%

Specific contribution of lamin A and lamin C in the development of laminopathies

Sylvius

Hathaway

Boudreau

et al. 2008

Experimental Cell Research

View full text Add to dashboard Cite

Mutations in the lamin A/C gene are involved in multiple human disorders for which the pathophysiological mechanisms are partially understood. Conflicting results prevail regarding the organization of lamin A and C mutants within the nuclear envelope (NE) and on the interactions of each lamin to its counterpart. We over-expressed various lamin A and C mutants both independently and together in COS7 cells. When expressed alone, lamin A with cardiac/muscular disorder mutations forms abnormal aggregates inside the NE and not inside the nucleoplasm. Conversely, the equivalent lamin C organizes as intranucleoplasmic aggregates that never connect to the NE as opposed to wild type lamin C. Interestingly, the lamin C molecules present within these aggregates exhibit an abnormal increased mobility. When co-expressed, the complex formed by lamin A/C aggregates in the NE. Lamin A and C mutants for lipodystrophy behave similarly to the wild type. These findings reveal that lamins A and C may be differentially affected depending on the mutation. This results in multiple possible physiological consequences which likely contribute in the phenotypic variability of laminopathies. The inability of lamin C mutants to join the nuclear rim in the absence of lamin A is a potential pathophysiological mechanism for laminopathies.

show abstract

Lamin A/C–dependent Localization of Nesprin-2, a Giant Scaffolder at the Nuclear Envelope

Cited by 155 publications

References 38 publications

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

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

UNC-83 Is a KASH Protein Required for Nuclear Migration and Is Recruited to the Outer Nuclear Membrane by a Physical Interaction with the SUN Protein UNC-84

Specific contribution of lamin A and lamin C in the development of laminopathies

Contact Info

Product

Resources

About