The Nuclear Envelope and Human Disease

Physiology ◽  
2004 ◽  
Vol 19 (5) ◽  
pp. 309-314 ◽  
Author(s):  
Antoine Muchir ◽  
Howard J. Worman
Keyword(s):  
Membrane Proteins ◽  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Intermediate Filament ◽  
Human Disease ◽  
Aging Process ◽  
Intermediate Filament Proteins ◽  
Inner Nuclear Membrane ◽  
Nuclear Lamins ◽  
Nuclear Lamin

Mutations in nuclear lamins A and C, intermediate filament proteins of the nuclear envelope, cause diseases affecting various tissues and the aging process. We review what is known about nuclear lamin function and the different diseases caused by mutations in lamins A and C and associated inner nuclear membrane proteins.

scholarly journals Fibroblasts lacking nuclear lamins do not have nuclear blebs or protrusions but nevertheless have frequent nuclear membrane ruptures

2018 ◽  
Vol 115 (40) ◽  
pp. 10100-10105 ◽  
Author(s):  
Natalie Y. Chen ◽  
Paul Kim ◽  
Thomas A. Weston ◽  
Lovelyn Edillo ◽  
Yiping Tu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Membrane Integrity ◽  
Nuclear Lamina ◽  
Virtual Absence ◽  
Inner Nuclear Membrane ◽  
Nuclear Lamins ◽  
Transmission Electron ◽  
Nuclear Lamin

The nuclear lamina, an intermediate filament meshwork lining the inner nuclear membrane, is formed by the nuclear lamins (lamins A, C, B1, and B2). Defects or deficiencies in individual nuclear lamin proteins have been reported to elicit nuclear blebs (protrusions or outpouchings of the nuclear envelope) and increase susceptibility for nuclear membrane ruptures. It is unclear, however, how a complete absence of nuclear lamins would affect nuclear envelope morphology and nuclear membrane integrity (i.e., whether nuclear membrane blebs or protrusions would occur and, if not, whether cells would be susceptible to nuclear membrane ruptures). To address these issues, we generated mouse embryonic fibroblasts (MEFs) lacking all nuclear lamins. The nuclear lamin-deficient MEFs had irregular nuclear shapes but no nuclear blebs or protrusions. Despite a virtual absence of nuclear blebs, MEFs lacking nuclear lamins had frequent, prolonged, and occasionally nonhealing nuclear membrane ruptures. By transmission electron microscopy, the inner nuclear membrane in nuclear lamin-deficient MEFs have a “wavy” appearance, and there were discrete discontinuities in the inner and outer nuclear membranes. Nuclear membrane ruptures were accompanied by a large increase in DNA damage, as judged by γ-H2AX foci. Mechanical stress increased both nuclear membrane ruptures and DNA damage, whereas minimizing transmission of cytoskeletal forces to the nucleus had the opposite effects.

Inner nuclear membrane proteins: impact on human disease

Chromosoma ◽  
2012 ◽  
Vol 121 (2) ◽  
pp. 153-167 ◽  
Author(s):  
Iván Méndez-López ◽  
Howard J. Worman
Keyword(s):  
Membrane Proteins ◽  
Nuclear Membrane ◽  
Human Disease ◽  
Inner Nuclear Membrane

scholarly journals Integral Membrane Proteins of the Nuclear Envelope Are Dispersed throughout the Endoplasmic Reticulum during Mitosis

1997 ◽  
Vol 137 (6) ◽  
pp. 1199-1210 ◽  
Author(s):  
Li Yang ◽  
Tinglu Guan ◽  
Larry Gerace
Keyword(s):  
Membrane Proteins ◽  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Mammalian Cells ◽  
Polyclonal Antibodies ◽  
Integral Membrane Proteins ◽  
Immunogold Electron Microscopy ◽  
Nuclear Pore ◽  
Nuclear Lamins ◽  
Nuclear Membranes

We have analyzed the fate of several integral membrane proteins of the nuclear envelope during mitosis in cultured mammalian cells to determine whether nuclear membrane proteins are present in a vesicle population distinct from bulk ER membranes after mitotic nuclear envelope disassembly or are dispersed throughout the ER. Using immunofluorescence staining and confocal microscopy, we compared the localization of two inner nuclear membrane proteins (laminaassociated polypeptides 1 and 2 [LAP1 and LAP2]) and a nuclear pore membrane protein (gp210) to the distribution of bulk ER membranes, which was determined with lipid dyes (DiOC6 and R6) and polyclonal antibodies. We found that at the resolution of this technique, the three nuclear envelope markers become completely dispersed throughout ER membranes during mitosis. In agreement with these results, we detected LAP1 in most membranes containing ER markers by immunogold electron microscopy of metaphase cells. Together, these findings indicate that nuclear membranes lose their identity as a subcompartment of the ER during mitosis. We found that nuclear lamins begin to reassemble around chromosomes at the end of mitosis at the same time as LAP1 and LAP2 and propose that reassembly of the nuclear envelope at the end of mitosis involves sorting of integral membrane proteins to chromosome surfaces by binding interactions with lamins and chromatin.

scholarly journals Regulated docking of nuclear membrane vesicles to vimentin filaments during mitosis.

1993 ◽  
Vol 123 (6) ◽  
pp. 1491-1505 ◽  
Author(s):  
C Maison ◽  
H Horstmann ◽  
S D Georgatos
Keyword(s):  
Nuclear Membrane ◽  
Magnetic Beads ◽  
Membrane Vesicles ◽  
Lamin B ◽  
Inner Nuclear Membrane ◽  
Endosomal Membrane ◽  
Nuclear Lamins ◽  
Nuclear Lamin ◽  
Vimentin Filaments

During mitosis, several types of intermediate-sized filaments (IFs) undergo an extensive remodelling in response to phosphorylation by cdc 2 and other protein kinases. However, unlike the nuclear lamins, the cytoplasmic IFs do not seem to follow a fixed disassembly stereotype and often retain their physical continuity without depolymerizing into soluble subunits. To investigate potential interactions between mitotically modified IFs and other cellular structures, we have examined prometaphase-arrested cells expressing the IF protein vimentin. We demonstrate here that vimentin filaments associate in situ and co-fractionate with a distinct population of mitotic vesicles. These vesicles carry on their surfaces nuclear lamin B, the inner nuclear membrane protein p58, and wheat germ agglutinin (WGA)-binding proteins. Consistent with a tight interaction between the IFs and the mitotic membranes, vimentin, nuclear lamin B, and a 180-kD WGA-binding protein are co-isolated when whole mitotic homogenates are incubated with anti-vimentin or anti-lamin B antibodies immobilized on magnetic beads. The vimentin-associated vesicles are essentially depleted of ER, Golgi and endosomal membrane proteins. The interaction of vimentin with lamin B-carrying membranes depends on phosphorylation and is weakened by dephosphorylation during nuclear reassembly in vitro. These observations reveal a novel interaction between IFs and cellular membranes and further suggest that the vimentin filaments may serve as a transient docking site for inner nuclear membrane vesicles during mitosis.

scholarly journals Lamin-dependent Localization of UNC-84, A Protein Required for Nuclear Migration in Caenorhabditis elegans

2002 ◽  
Vol 13 (3) ◽  
pp. 892-901 ◽  
Author(s):  
Kenneth K. Lee ◽  
Daniel Starr ◽  
Merav Cohen ◽  
Jun Liu ◽  
Min Han ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Membrane Proteins ◽  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Nuclear Periphery ◽  
Nuclear Migration ◽  
Cell Stage ◽  
Inner Nuclear Membrane ◽  
Late Anaphase

Mutations in the Caenorhabditis elegans unc-84 gene cause defects in nuclear migration and anchoring. We show that endogenous UNC-84 protein colocalizes with Ce-lamin at the nuclear envelope and that the envelope localization of UNC-84 requires Ce-lamin. We also show that during mitosis, UNC-84 remains at the nuclear periphery until late anaphase, similar to known inner nuclear membrane proteins. UNC-84 protein is first detected at the 26-cell stage and thereafter is present in most cells during development and in adults. UNC-84 is properly expressed in unc-83 andanc-1 lines, which have phenotypes similar tounc-84, suggesting that neither the expression nor nuclear envelope localization of UNC-84 depends on UNC-83 or ANC-1 proteins. The envelope localization of Ce-lamin, Ce-emerin, Ce-MAN1, and nucleoporins are unaffected by the loss of UNC-84. UNC-84 is not required for centrosome attachment to the nucleus because centrosomes are localized normally in unc-84 hyp7 cells despite a nuclear migration defect. Models for UNC-84 localization are discussed.

scholarly journals System analysis shows distinct mechanisms and common principles of nuclear envelope protein dynamics

2011 ◽  
Vol 193 (1) ◽  
pp. 109-123 ◽  
Author(s):  
Nikolaj Zuleger ◽  
David A. Kelly ◽  
A. Christine Richardson ◽  
Alastair R. W. Kerr ◽  
Martin W. Goldberg ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
System Analysis ◽  
Nuclear Pore ◽  
Binding Affinities ◽  
Inner Nuclear Membrane ◽  
Wide Range ◽  
Recovery Times

The nuclear envelope contains >100 transmembrane proteins that continuously exchange with the endoplasmic reticulum and move within the nuclear membranes. To better understand the organization and dynamics of this system, we compared the trafficking of 15 integral nuclear envelope proteins using FRAP. A surprising 30-fold range of mobilities was observed. The dynamic behavior of several of these proteins was also analyzed after depletion of ATP and/or Ran, two functions implicated in endoplasmic reticulum–inner nuclear membrane translocation. This revealed that ATP- and Ran-dependent translocation mechanisms are distinct and not used by all inner nuclear membrane proteins. The Ran-dependent mechanism requires the phenylalanine-glycine (FG)-nucleoporin Nup35, which is consistent with use of the nuclear pore complex peripheral channels. Intriguingly, the addition of FGs to membrane proteins reduces FRAP recovery times, and this also depends on Nup35. Modeling of three proteins that were unaffected by either ATP or Ran depletion indicates that the wide range in mobilities could be explained by differences in binding affinities in the inner nuclear membrane.

scholarly journals The CaaX motif is required for isoprenylation, carboxyl methylation, and nuclear membrane association of lamin B2.

1991 ◽  
Vol 113 (1) ◽  
pp. 13-23 ◽  
Author(s):  
G T Kitten ◽  
E A Nigg
Keyword(s):  
Nuclear Membrane ◽  
Stop Codon ◽  
Mevalonic Acid ◽  
Cysteine Residue ◽  
Inner Nuclear Membrane ◽  
Nuclear Lamins ◽  
Carboxyl Methylation ◽  
Reticulocyte Lysates ◽  
Caax Motif

Recent evidence suggests that the conserved COOH-terminal CaaX motif of nuclear lamins may play a role in targeting newly synthesized proteins to the nuclear envelope. We have shown previously that in rabbit reticulocyte lysates the cysteine residue of the CaaX motif of chicken lamin B2 is necessary for incorporation of a derivative of mevalonic acid, the precursor of isoprenoids. Here we have analyzed the properties of normal and mutated forms of chicken lamin B2 stably expressed in mouse L cells. Mutation of the cysteine residue of the CaaX motif to alanine or introduction of a stop codon immediately after the cysteine residue was found to abolish both isoprenylation and carboxyl methylation of transfected lamin B2. Concomitantly, although nuclear import of the mutant lamin B2 proteins was preserved, their association with the inner nuclear membrane was severely impaired. From these results we conclude that the COOH-terminal CaaX motif is required for isoprenylation and carboxyl methylation of lamins in vivo, and that these modifications are important for association of B-type lamins with the nucleoplasmic surface of the inner nuclear membrane.

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