scholarly journals Decreased torsinA or LINC Complex Function Rescues a Laminopathy in Caenorhabditis elegans

2020 ◽  
Author(s):  
Gabriela Huelgas-Morales ◽  
Mark Sanders ◽  
Gemechu Mekonnen ◽  
Tatsuya Tsukamoto ◽  
David Greenstein
Keyword(s):  
Nuclear Envelope ◽  
Complex Function ◽  
Nuclear Lamina ◽  
Premature Aging ◽  
Linc Complex ◽  
Force Transmission ◽  
Complex Activity ◽  
Aaa Atpase ◽  
C Elegans ◽  
Associated Proteins

AbstractThe function of the nucleus depends on the integrity of the nuclear lamina, an intermediate filament network associated with the linker of nucleoskeleton and cytoskeleton (LINC) complex spanning the nuclear envelope. In turn, the AAA+ ATPase torsinA regulates force transmission from the cytoskeleton to the nucleus. In humans, mutations affecting nuclear envelope-associated proteins cause laminopathies, including progeria, myopathy, and dystonia. We report that decreasing the function of the C. elegans torsinA homolog, OOC-5, rescues the sterility and premature aging caused by a null mutation in the single worm lamin homolog, lmn-1. Loss of OOC-5 activity prevents nuclear collapse in lmn-1 mutants by disrupting the function of the LINC complex. These results suggest that LINC complex-transmitted forces damage nuclei with a compromised nuclear lamina.One Sentence SummaryInhibiting LINC complex activity prevents a progeric syndrome in C. elegans.

scholarly journals Decreased mechanotransduction prevents nuclear collapse in aCaenorhabditis eleganslaminopathy

2020 ◽  
Vol 117 (49) ◽  
pp. 31301-31308
Author(s):  
Gabriela Huelgas-Morales ◽  
Mark Sanders ◽  
Gemechu Mekonnen ◽  
Tatsuya Tsukamoto ◽  
David Greenstein
Keyword(s):  
Nuclear Envelope ◽  
Complex Function ◽  
Nuclear Lamina ◽  
Premature Aging ◽  
Nuclear Pore ◽  
Linc Complex ◽  
Force Transmission ◽  
Cell Nuclei ◽  
Aaa Atpase ◽  
C Elegans

The function of the nucleus depends on the integrity of the nuclear lamina, an intermediate filament network associated with the linker of nucleoskeleton and cytoskeleton (LINC) complex. The LINC complex spans the nuclear envelope and mediates nuclear mechanotransduction, the process by which mechanical signals and forces are transmitted across the nuclear envelope. In turn, the AAA+ ATPase torsinA is thought to regulate force transmission from the cytoskeleton to the nucleus. In humans, mutations affecting nuclear envelope-associated proteins cause laminopathies, including progeria, myopathy, and dystonia, though the extent to which endogenous mechanical stresses contribute to these pathologies is unclear. Here, we use theCaenorhabditis elegansgermline as a model to investigate mechanisms that maintain nuclear integrity as germ cell nuclei progress through meiotic development and migrate for gametogenesis—processes that require LINC complex function. We report that decreasing the function of theC. eleganstorsinA homolog, OOC-5, rescues the sterility and premature aging caused by a null mutation in the single worm lamin homolog. We show that decreasing OOC-5/torsinA activity prevents nuclear collapse in lamin mutants by disrupting the function of the LINC complex. At a mechanistic level, OOC-5/torsinA promotes the assembly or maintenance of the lamin-associated LINC complex and this activity is also important for interphase nuclear pore complex insertion into growing germline nuclei. These results demonstrate that LINC complex-transmitted forces damage nuclei with a compromised nuclear lamina. Thus, the torsinA–LINC complex nexus might comprise a therapeutic target for certain laminopathies by preventing damage from endogenous cellular forces.

scholarly journals Keeping the LINC: the importance of nucleocytoskeletal coupling in intracellular force transmission and cellular function

2011 ◽  
Vol 39 (6) ◽  
pp. 1729-1734 ◽  
Author(s):  
Maria L. Lombardi ◽  
Jan Lammerding
Keyword(s):  
Nuclear Envelope ◽  
Complex Function ◽  
Cell Polarization ◽  
Mechanical Stimuli ◽  
Linc Complex ◽  
Force Transmission ◽  
Cellular Functions ◽  
Nuclear Lamins ◽  
Wide Range ◽  
Filament Networks

Providing a stable physical connection between the nucleus and the cytoskeleton is essential for a wide range of cellular functions and it could also participate in mechanosensing by transmitting intra- and extra-cellular mechanical stimuli via the cytoskeleton to the nucleus. Nesprins and SUN proteins, located at the nuclear envelope, form the LINC (linker of nucleoskeleton and cytoskeleton) complex that connects the nucleus to the cytoskeleton; underlying nuclear lamins contribute to anchoring LINC complex components at the nuclear envelope. Disruption of the LINC complex or loss of lamins can result in disturbed perinuclear actin and intermediate filament networks and causes severe functional defects, including impaired nuclear positioning, cell polarization and cell motility. Recent studies have identified the LINC complex as the major force-transmitting element at the nuclear envelope and suggest that many of the aforementioned defects can be attributed to disturbed force transmission between the nucleus and the cytoskeleton. Thus mutations in nesprins, SUN proteins or lamins, which have been linked to muscular dystrophies and cardiomyopathies, may weaken or completely eliminate LINC complex function at the nuclear envelope and result in impaired intracellular force transmission, thereby disrupting critical cellular functions.

scholarly journals The LINC complex transmits integrin-dependent tension to the nuclear lamina and represses epidermal differentiation

2020 ◽  
Author(s):  
Emma Carley ◽  
Rachel K. Stewart ◽  
Abigail Zieman ◽  
Iman Jalilian ◽  
Diane. E. King ◽  
...  
Keyword(s):  
Cell Fate ◽  
Control Cell ◽  
Nuclear Lamina ◽  
Epidermal Differentiation ◽  
Keratinocyte Differentiation ◽  
Linc Complex ◽  
Force Transmission ◽  
Cell Fate Decisions

AbstractWhile the mechanisms by which chemical signals control cell fate have been well studied, how mechanical inputs impact cell fate decisions are not well understood. Here, using the well-defined system of keratinocyte differentiation in the skin, we examine whether and how direct force transmission to the nucleus regulates epidermal cell fate. Using a molecular biosensor, we find that tension on the nucleus through Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes requires integrin engagement in undifferentiated epidermal stem cells, and is released during differentiation concomitant with decreased tension on A-type lamins. LINC complex ablation in mice reveals that LINC complexes are required to repress epidermal differentiation in vivo and in vitro and influence accessibility of epidermal differentiation genes, suggesting that force transduction from engaged integrins to the nucleus plays a role in maintaining keratinocyte progenitors. This work reveals a direct mechanotransduction pathway capable of relaying adhesion-specific signals to regulate cell fate.

scholarly journals Nuclear envelope rupture is induced by actin-based nucleus confinement

2016 ◽  
Vol 215 (1) ◽  
pp. 27-36 ◽  
Author(s):  
Emily M. Hatch ◽  
Martin W. Hetzer
Keyword(s):  
Nuclear Envelope ◽  
Cancer Cells ◽  
Nuclear Membrane ◽  
Nuclear Lamina ◽  
Membrane Stability ◽  
Linc Complex ◽  
Actin Bundles ◽  
In Cells

Repeated rounds of nuclear envelope (NE) rupture and repair have been observed in laminopathy and cancer cells and result in intermittent loss of nucleus compartmentalization. Currently, the causes of NE rupture are unclear. Here, we show that NE rupture in cancer cells relies on the assembly of contractile actin bundles that interact with the nucleus via the linker of nucleoskeleton and cytoskeleton (LINC) complex. We found that the loss of actin bundles or the LINC complex did not rescue nuclear lamina defects, a previously identified determinant of nuclear membrane stability, but did decrease the number and size of chromatin hernias. Finally, NE rupture inhibition could be rescued in cells treated with actin-depolymerizing drugs by mechanically constraining nucleus height. These data suggest a model of NE rupture where weak membrane areas, caused by defects in lamina organization, rupture because of an increase in intranuclear pressure from actin-based nucleus confinement.

scholarly journals A Balance Between Intermediate Filaments and Microtubules Maintains Nuclear Architecture in the Cardiomyocyte

2020 ◽  
Vol 126 (3) ◽  
Author(s):  
Julie Heffler ◽  
Parisha P. Shah ◽  
Patrick Robison ◽  
Sai Phyo ◽  
Kimberly Veliz ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Intermediate Filaments ◽  
Genome Organization ◽  
Contractile Function ◽  
Nuclear Architecture ◽  
Super Resolution ◽  
Nuclear Lamina ◽  
Linc Complex ◽  
Spectrin Repeat ◽  
Balance Of Forces

Rationale: Mechanical forces are transduced to nuclear responses via the linkers of the nucleoskeleton and cytoskeleton (LINC) complex, which couples the cytoskeleton to the nuclear lamina and associated chromatin. While disruption of the LINC complex can cause cardiomyopathy, the relevant interactions that bridge the nucleoskeleton to cytoskeleton are poorly understood in the cardiomyocyte, where cytoskeletal organization is unique. Furthermore, while microtubules and desmin intermediate filaments associate closely with cardiomyocyte nuclei, the importance of these interactions is unknown. Objective: Here, we sought to determine how cytoskeletal interactions with the LINC complex regulate nuclear homeostasis in the cardiomyocyte. Methods and Results: To this end, we acutely disrupted the LINC complex, microtubules, actin, and intermediate filaments and assessed the consequences on nuclear morphology and genome organization in rat ventricular cardiomyocytes via a combination of super-resolution imaging, biophysical, and genomic approaches. We find that a balance of dynamic microtubules and desmin intermediate filaments is required to maintain nuclear shape and the fidelity of the nuclear envelope and lamina. Upon depletion of desmin (or nesprin [nuclear envelope spectrin repeat protein]-3, its binding partner in the LINC complex), polymerizing microtubules collapse the nucleus and drive infolding of the nuclear membrane. This results in DNA damage, a loss of genome organization, and broad transcriptional changes. The collapse in nuclear integrity is concomitant with compromised contractile function and may contribute to the pathophysiological changes observed in desmin-related myopathies. Conclusions: Disrupting the tethering of desmin to the nucleus results in a loss of nuclear homeostasis and rapid alterations to cardiomyocyte function. Our data suggest that a balance of forces imposed by intermediate filaments and microtubules is required to maintain nuclear structure and genome organization in the cardiomyocyte.

scholarly journals Nuclear envelope organization in Dictyostelium discoideum

2019 ◽  
Vol 63 (8-9-10) ◽  
pp. 509-519 ◽  
Author(s):  
Petros Batsios ◽  
Ralph Gräf ◽  
Michael P. Koonce ◽  
Denis A. Larochelle ◽  
Irene Meyer
Keyword(s):  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Nuclear Lamina ◽  
Major Constituent ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Linc Complex ◽  
Family Protein ◽  
Import And Export ◽  
Pore Complexes

The nuclear envelope consists of the outer and the inner nuclear membrane, the nuclear lamina and the nuclear pore complexes, which regulate nuclear import and export. The major constituent of the nuclear lamina of Dictyostelium is the lamin NE81. It can form filaments like B-type lamins and it interacts with Sun1, as well as with the LEM/HeH-family protein Src1. Sun1 and Src1 are nuclear envelope transmembrane proteins involved in the centrosome-nucleus connection and nuclear envelope stability at the nucleolar regions, respectively. In conjunction with a KASH-domain protein, Sun1 usually forms a so-called LINC complex. Two proteins with functions reminiscent of KASH-domain proteins at the outer nuclear membrane of Dictyostelium are known; interaptin which serves as an actin connector and the kinesin Kif9 which plays a role in the microtubule-centrosome connector. However, both of these lack the conserved KASH-domain. The link of the centrosome to the nuclear envelope is essential for the insertion of the centrosome into the nuclear envelope and the appropriate spindle formation. Moreover, centrosome insertion is involved in permeabilization of the mitotic nucleus, which ensures access of tubulin dimers and spindle assembly factors. Our recent progress in identifying key molecular players at the nuclear envelope of Dictyostelium promises further insights into the mechanisms of nuclear envelope dynamics.

scholarly journals Keratins couple with the nuclear lamina and regulate proliferation in colonic epithelial cells

2020 ◽  
Author(s):  
Carl-Gustaf A. Stenvall ◽  
Joel H. Nyström ◽  
Ciarán Butler-Hallissey ◽  
Stephen A. Adam ◽  
Roland Foisner ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Nuclear Structure ◽  
Mechanical Stability ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Intestinal Epithelial ◽  
Linc Complex ◽  
Colonic Inflammation ◽  
Associated Proteins

AbstractKeratin intermediate filaments (IFs) convey mechanical stability and protection against stress to epithelial cells, and may participate in nuclear structure and organization. Keratins are important for colon health as observed in keratin 8 knockout (K8−/−) mice, which exhibit colonic inflammation and epithelial hyperproliferation. Here, using a full body and two intestinal epithelial-specific K8−/− knockout mouse models, we determine if cytoplasmic keratins affect the nuclear structure and lamina in epithelial colonocytes. K8−/− colonocytes in vivo and in organoid cultures exhibit significantly decreased levels of the major lamins A/C, B1 and B2 in a colon-specific and cell-intrinsic manner independent of major changes in colonic inflammation or microbiota. Downregulation of K8 by siRNA in Caco-2 cells similarly decreases lamin A levels, which recover after re-expression of K8. K8 loss is associated with reduced plectin, LINC complex proteins and lamin-associated proteins, indicating a dysfunctional keratin-nuclear lamina coupling. Immunoprecipitation identifies complexes of colonocyte keratins with the LINC protein SUN2 and lamin A. Hyperphosphorylation of the lamin A-associated cell cycle regulator pRb in K8−/− colonocytes together with increased nuclear localization of the mechanosensor YAP provide a molecular mechanism for the hyperproliferation phenotype. These findings identify a novel, colonocyte-specific role for K8 in nuclear function.

Relationships at the nuclear envelope: lamins and nuclear pore complexes in animals and plants

2010 ◽  
Vol 38 (3) ◽  
pp. 829-831 ◽  
Author(s):  
Jindriska Fiserova ◽  
Martin W. Goldberg
Keyword(s):  
Nuclear Envelope ◽  
Nuclear Periphery ◽  
Nuclear Lamina ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Nucleocytoplasmic Trafficking ◽  
Animal Cells ◽  
Cellular Processes ◽  
Associated Proteins ◽  
Pore Complexes

The nuclear envelope comprises a distinct compartment at the nuclear periphery that provides a platform for communication between the nucleus and cytoplasm. Signal transfer can proceed by multiple means. Primarily, this is by nucleocytoplasmic trafficking facilitated by NPCs (nuclear pore complexes). Recently, it has been indicated that signals can be transmitted from the cytoskeleton to the intranuclear structures via interlinking transmembrane proteins. In animal cells, the nuclear lamina tightly underlies the inner nuclear membrane and thus represents the protein structure located at the furthest boundary of the nucleus. It enables communication between the nucleus and the cytoplasm via its interactions with chromatin-binding proteins, transmembrane and membrane-associated proteins. Of particular interest is the interaction of the nuclear lamina with NPCs. As both structures fulfil essential roles in close proximity at the nuclear periphery, their interactions have a large impact on cellular processes resulting in affects on tissue differentiation and development. The present review concentrates on the structural and functional lamina–NPC relationship in animal cells and its potential implications to plants.

scholarly journals RASCAL Is a New Human Cytomegalovirus-Encoded Protein That Localizes to the Nuclear Lamina and in Cytoplasmic Vesicles at Late Times Postinfection

2010 ◽  
Vol 84 (13) ◽  
pp. 6483-6496 ◽  
Author(s):  
Matthew S. Miller ◽  
Wendy E. Furlong ◽  
Leesa Pennell ◽  
Marc Geadah ◽  
Laura Hertel
Keyword(s):  
Amino Acids ◽  
Nuclear Envelope ◽  
Human Cytomegalovirus ◽  
Nuclear Membrane ◽  
Nuclear Lamina ◽  
Open Reading Frames ◽  
Short Version ◽  
Nuclear Egress ◽  
Cytoplasmic Vesicles ◽  
Associated Proteins

ABSTRACT The products of numerous open reading frames (ORFs) present in the genome of human cytomegalovirus (CMV) have not been characterized. Here, we describe the identification of a new CMV protein localizing to the nuclear envelope and in cytoplasmic vesicles at late times postinfection. Based on this distinctive localization pattern, we called this new protein nuclear r im- as sociated c ytomegalovir al protein, or RASCAL. Two RASCAL isoforms exist, a short version of 97 amino acids encoded by the majority of CMV strains and a longer version of 176 amino acids encoded by the Towne, Toledo, HAN20, and HAN38 strains. Both isoforms colocalize with lamin B in deep intranuclear invaginations of the inner nuclear membrane (INM) and in novel cytoplasmic vesicular structures possibly derived from the nuclear envelope. INM infoldings have been previously described as sites of nucleocapsid egress, which is mediated by the localized disruption of the nuclear lamina, promoted by the activities of viral and cellular kinases recruited by the lamina-associated proteins UL50 and UL53. RASCAL accumulation at the nuclear membrane required the presence of UL50 but not of UL53. RASCAL and UL50 also appeared to specifically interact, suggesting that RASCAL is a new component of the nuclear egress complex (NEC) and possibly involved in mediating nucleocapsid egress from the nucleus. Finally, the presence of RASCAL within cytoplasmic vesicles raises the intriguing possibility that this protein might participate in additional steps of virion maturation occurring after capsid release from the nucleus.

scholarly journals Ablation of SUN2-containing LINC complexes drives cardiac hypertrophy without interstitial fibrosis

2019 ◽  
Vol 30 (14) ◽  
pp. 1664-1675 ◽  
Author(s):  
Rachel M. Stewart ◽  
Elisa C. Rodriguez ◽  
Megan C. King
Keyword(s):  
Cardiac Hypertrophy ◽  
Nuclear Envelope ◽  
Interstitial Fibrosis ◽  
Nuclear Lamina ◽  
Mapk Signaling ◽  
Negative Regulator ◽  
Linc Complex ◽  
Tgfβ Signaling ◽  
Disease Etiology ◽  
New Perspective

The cardiomyocyte cytoskeleton, including the sarcomeric contractile apparatus, forms a cohesive network with cellular adhesions at the plasma membrane and nuclear–­cytoskeletal linkages (LINC complexes) at the nuclear envelope. Human cardiomyopathies are genetically linked to the LINC complex and A-type lamins, but a full understanding of disease etiology in these patients is lacking. Here we show that SUN2-null mice display cardiac hypertrophy coincident with enhanced AKT/MAPK signaling, as has been described previously for mice lacking A-type lamins. Surprisingly, in contrast to lamin A/C-null mice, SUN2-null mice fail to show coincident fibrosis or upregulation of pathological hypertrophy markers. Thus, cardiac hypertrophy is uncoupled from profibrotic signaling in this mouse model, which we tie to a requirement for the LINC complex in productive TGFβ signaling. In the absence of SUN2, we detect elevated levels of the integral inner nuclear membrane protein MAN1, an established negative regulator of TGFβ signaling, at the nuclear envelope. We suggest that A-type lamins and SUN2 play antagonistic roles in the modulation of profibrotic signaling through opposite effects on MAN1 levels at the nuclear lamina, suggesting a new perspective on disease etiology.

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