Introduction

The eukaryotic nucleus contains the chromosomes and is a complex organelle where major cellular processes, such as DNA replication, RNA transcription and processing, and ribosome assembly take place. The function of the nucleus highly depends on its structural organization and the dynamic structural rearrangements occurring in cell differentiation and cell cycle progression.¹ Cellular structures and proteins involved in nuclear architecture are not very well understood except for a few major elements. The nuclear envelope (NE) enwraps the DNA and forms the border between the nucleus and cytoplasm. It is composed of inner and outer nuclear membranes that are separated by the perinuclear space and contain nuclear pore complexes mediating nucleo-cytoplasmic transport. The outer nuclear membrane is continuous with the endoplasmic reticulum and is also directly linked to the inner membrane at sites of nuclear pore complexes (Fig. 1). Despite the continuity of membrane structures, protein and lipid composition and functions of inner and outer membranes are clearly different, most likely due to specific interactions of membrane components with nuclear and cytoplasmic components, respectively. Underneath the inner membrane is a meshwork of nuclear-specific intermediate filaments, termed the nuclear lamina, which includes lamins plus a growing number of lamin-associated proteins, which regulate lamin assembly and function.^1,2 Most of these lamin-binding proteins have been identified as integral membrane proteins of the inner membrane or are tightly associated with the lipid bilayer.^2-4 Biochemically, the nuclear lamina is defined as the peripheral nuclear structure that remains insoluble after extraction of nuclei with non-ionic detergents, salt and nucleases.^5,6 However, the lamina is only a subfraction of the detergent-salt-resistant structural framework, which runs throughout the nuclear interior and organizes nuclear space and is often referred to as nucleoskeleton or nuclear matrix.⁷ As the visualization of this putative nuclear scaffold has always been hampered by the bulky chromatin mass, it is still under debate, whether there exists a chromatin-independent proteinaceous nuclear scaffold or whether intranuclear structures are organized by a complex network of protein-protein, protein-DNA and protein-RNA interactions.⁸ In any case, the nuclear scaffold is supposed to provide mechanical stability for nuclear structure, to form a platform for most metabolic nuclear processes, and to organize chromatin in a three-dimensional nuclear space and thus regulate gene expression at the chromatin structure level. Except for the peripheral lamins, the components and molecular organization of the nucleoskeleton are not very well understood.

Figure 1

Schematic drawing of the molecular links at the interface between the nuclear envelope and the internal nucleoskeleton/chromatin scaffold. Arrows denote specific interactions of components shown in vitro and/or in vivo. For details see text.

In this review, I summarize the major components and interactions of the lamina and focus on the interface between the peripheral nuclear envelope and the intranuclear scaffold/chromatin. I will also describe cell cycle-dependent dynamics and potential functions of these interactions, particularly focusing on members of the Lamina-Associated Polypeptide 2 (LAP2) family, whose cell cycle-dependent dynamics have been fairly well characterized in the past years.

Major Components of the Peripheral Nuclear Lamina

The core structure of the nuclear lamina is formed by type V intermediate filament proteins, the lamins.⁹ They assemble to a meshwork of tetragonally organized 10-nm filaments underneath the inner nuclear membrane. The number and complexity of lamins has increased during metazoan evolution. Vertebrates have three lamin genes (LMNA, LMNB1, LMNB2) encoding at least seven distinct isoforms.² B-type lamins are constitutively expressed in cells throughout development and every cell expresses at least one B-type lamin. A-type lamins, comprising lamin A and its smaller splice variant lamin C are only expressed in later stages of development and in differentiated cells.²

The assembly and attachment of lamins at the membrane involve several mechanisms and are different between A- and B-type lamins. B-type lamins contain a stable C-terminal farnesyl modification, which is important but not sufficient for targeting and anchoring the protein to the membrane.^10-13 In contrast, lamin A is only transiently farnesylated due to cleavage of the C-terminal residues containing the farnesyl group during protein maturation, and lamin C is never farnesylated.¹⁰ Therefore, B-type lamins are more tightly associated with membrane structures than A-type lamins in mitosis and interphase and are less stably incorporated into the lamina.^14,15

Homotypic interactions of lamin subunits,⁹ hetero-oligomeric interactions of B-type and A-type lamin dimers or oligomers,¹¹ as well as interactions of lamins with integral and peripheral membrane proteins are essential for the proper assembly of the lamina underneath the nuclear membrane. Most of the lamin-binding proteins are tightly bound to lamins and cofractionate with lamins even after detergent-salt extraction of nuclei or of isolated NE fractions.^5,6,16-18 Therefore, these proteins are considered as genuine components of the nuclear lamina. Among those are (see Fig. 1):

The Lamin B receptor (LBR, p58) contains eight transmembrane domains¹⁹ and was found to interact with B-type lamins in vivo and in vitro.^20-22 Since ectopically expressed lamin B1 mutants lacking farnesylation segregate independently of LBR,¹² it was suggested that LBR might also bind to the farnesyl residues of B-type lamins. The hydrophobic domain of LBR shares extensive homology with sterol reductases and exhibits C14 reductase activity, suggesting that the protein might have additional functions in sterol metabolism.^23,24

Lamina-associated-polypeptide 1 (LAP-1) is a type II integral nuclear membrane protein, containing a nucleoplasmic N-terminus, a single transmembrane spanning region, and a C-terminus located in the luminal space between inner and outer nuclear membrane.²⁵ LAP1 specifically interacts with A-type lamins in vitro⁶ and its nuclear envelope localization depends on the presence of lamin A in vivo.²⁶ LAP1 exists as three alternatively spliced isoforms, the smallest one, LAP1C, being expressed constitutively, while the larger isoforms, LAP1 A and B, which contain additional domains in the nucleoplasm, are expressed only in differentiated cells like A-type lamins.²⁵

Lamina-associated polypeptide 2 (LAP2) is another family of alternatively spliced lamin binding proteins, comprising up to six mammalian isoforms, LAP2α, β, γ, δ, ϵ, and ζ^27,28 (formerly also called thymopoietins) and three Xenopus LAP2 proteins.^29,30 Except for LAP2α and LAP2ζ, all mammalian LAP2 isoforms contain a closely related N-terminal nucleoplasmic domain of variable length and share a single transmembrane spanning region passing the inner nuclear membrane, and a short C-terminus located in the luminal space between inner and outer nuclear membrane.³¹ LAP2β possesses the longest nucleoplasmic N-terminus (223aa), LAP2 e, d, g miss regions of 40, 72, and 109 amino acids respectively due to alternative splicing, but are otherwise identical, and LAP2ζ represents a truncated form of LAP2β, missing 190 amino acids of the nucleoplasmic domain as well as the transmembrane and luminal regions. LAP2α is structurally and functionally different from the other isoforms. It shares only the N-terminal 187 amino acids with all the other LAP2 isoforms but contains a unique C-terminus (506 aa) lacking a transmembrane domain. Unlike LAP2α, LAP2β was found to interact with lamin B in vitro.⁶ Its lamin B-interaction domain was located within a 72-amino acid long stretch in the nucleoplasmic region (aa 298-370),³² which is also present in the smaller isoforms LAP2ϵ and d, and parts of it in LAP2γ. An interaction of the smaller isoforms with lamin B, however, has not been demonstrated experimentally. LAP2α is unique, as it is located in the nuclear interior³³ and binds specifically intranuclear A-type lamins³⁴ (see below). Very little is known about the expression patterns of the various LAP2 isoforms. Northern blot analysis and S1-nuclease protection assays revealed that LAP2 mRNAs are ubiquitously found in many tissues and cells of human, mouse and rat origin.^27,28,35 At the protein level, LAP2α and β appear to be the predominantly expressed LAP2 isoforms in mammalian cells,^27,33,36 but a recent proteomics analysis aimed at characterizing novel NE proteins clearly revealed also expression of smaller LAP2 isoforms.³⁷ While available data on the mammalian LAP2 isoforms indicate an ubiquitous expression, some of the LAP2 homologues, identified in Xenopus,^29,30 showed differential expression during development. One of them was found to be expressed only in somatic cells, but was not detected in oocytes, eggs and in early embryos up to the gastrula stage, while a slightly larger putative LAP2 isoform—which has not been cloned yet—was predominantly expressed in Xenopus eggs and embryos and was downregulated during embryogenesis.²⁹

Emerin and MAN1 are proteins related to LAP2 isoforms. These proteins share a ˜40 amino acid long highly homologous structural motif (LEM domain) in their N-termini¹⁷, which consists of a helical turn and two large parallel α-helices connected by a 11 to 12 residue loop.^38,39 Emerin is a ubiquitously expressed type II integral membrane protein of the inner nuclear membrane^18,40 and has been identified as the gene product that is missing or mutated in patients suffering from X-linked Emery-Dreifuss muscular dystrophy (EDMD).^41,42 It binds to both A- and B-type lamins in vitro ^43-45 and its nuclear envelope localization is dependent on the expression of lamin A.^46,47 MAN1 is a lamina-associated protein detected by the MAN autoimmune serum,⁴⁸ and by sequence analysis is predicted to contain two transmembrane domains.¹⁷ Its interaction with lamins has not been analyzed yet.

A visual screen of a GFP-fusion library⁴⁹ and a proteomics approach³⁷ revealed novel integral membrane proteins termed nurim, with 5 predicted transmembrane domains and only few hydrophilic residues, Unc-84, a protein similar to Drosophila Unc-84⁵⁰ and a novel protein LUMA with three to four predicted transmembrane domains. Binding of these proteins to lamins has not been analyzed yet.

In addition, a peripheral membrane protein, otefin,^51,52 has been identified as a lamina protein in Drosophila.

Lamina Proteins in the Nuclear Interior

Lamins were traditionally regarded as proteins of the nuclear periphery, but with the availability of novel tools and microscopic techniques the concept of intranuclear lamins has recently developed. Since the nuclear membrane forms extensive tubular invaginations projecting deep into the nuclear interior,⁵³ it is often hard to distinguish whether observed internal lamin structures are still associated with the invaginated nuclear membrane or whether they are truly intranuclear, apart from the nuclear membrane. Nevertheless, specific antibodies,^34,54 several microscopical preparations techniques,^55,56 and the use of expressed green fluorescent protein-(GFP) fusions of lamins,^57,58 have revealed intranuclear lamin structures in foci or along filamentous structures or diffusely distributed throughout the nuclear interior. Although B-type lamins may also localize to intranuclear replication sites⁵⁹ and a minor fraction of GFP-lamin B has been detected in stable intranuclear structures by fluorescence recovery after photobleaching (FRAP) analysis,⁵⁸ the majority of studies have revealed particularly A-type lamins in the nuclear interior. This observation is consistent with the lack of C-terminal farnesyl modification of mature A-type lamins and the less stable association with the peripheral nuclear membrane and the nuclear lamina as compared with B-type lamins (see above).

Intranuclear A-type lamins may exist in a complex with LAP2α, the only LAP2 isoform not integrated into the membrane. LAP2α is a nucleoskeletal protein, based on its resistance to extraction by detergents and high salt,³³ and was found to directly interact with the C-terminal tail region of mature lamins A and C in vitro.³⁴ Furthermore, selective disruption of endogenous lamin A structures upon ectopic expression of dominant-negative lamin mutants in Hela cells caused a relocalization of LAP2α to intranuclear lamin A/C aggregates, but had no effect on lamin B, LAP2β, or NuMa.³⁴ It is still unclear, however, whether lamin A and LAP2α form filaments or other higher order structures of the nuclear scaffold, or whether they exist as smaller complexes involved in the regulation of nuclear processes (see below). It is also not known, whether there is continuity between peripheral and internal nuclear lamin A structures or whether lamin subunits steadily exchange between these two subnuclear compartments.

Several laboratories have reported a transient localization of A-type lamins in the nuclear interior before their assembly into the nuclear lamina. FRAP analyses in GFP-lamin A expressing cells showed that the assembly of lamin A into peripheral nuclear structures is a late event in post-mitotic nuclear reformation,⁵⁸ leading to accumulation of the majority of lamins A and C in the nuclear interior in G1 phase.^34,60 Furthermore, microinjected lamin A and/or lamin C were found to first accumulate in nucleoplasmic foci, before the majority was incorporated into the nuclear lamina.^61,62 As non-processed lamin A (missing the farnesyl modification) accumulated in similar intranuclear foci,^63,64 transient intranuclear localization of lamin A might be directly linked to its post-translational processing, but the molecular mechanisms remain unclear. Recently, a novel nuclear protein of unknown cellular function, Narf, has been identified by yeast two-hybrid-screens as a direct and specific interaction partner of unprocessed lamin A.⁶⁵

Farnesylation and C-terminal proteolytic cleavage of A-type lamins during maturation can, however, not be the only reason for their transient accumulation in the nucleus, as intranuclear lamin A found in late stages of post-mitotic nuclear reformation is fully processed, and lamin C, which was also found to accumulate in intranuclear structures,⁶² is not processed at all. Thus, other modifications such as (de-) phosphorylation,⁶⁶ or specific interactions with still unknown nuclear proteins might also be required for correct targeting of A-type lamins to peripheral as well as intranuclear structures.

Interactions at the Interface Between the Lamina and the Nuclear Scaffold/Chromatin

The transcriptionally silenced or less active and late replicating domains in higher eukaryotic genomes, referred to as heterochromatin, are dynamically associated with the NE.^67-69 This association involves a complex network of specific protein-protein and protein-DNA interactions at the interface of the lamina and the nuclear matrix (Fig. 1). In vitro, A and B-type lamins have been shown to bind directly to matrix/scaffold attachment regions^70,71 and to telomeric and heterochromatic DNA sequences,^72,73 but the physiological relevance of these associations is not clear. However, photo-crosslinking experiments in Drosophila cells revealed specific association of interphase lamins with DNA in vivo.⁷⁴ Lamins can also interact with and assemble around chromatin, and this is mediated by the lamin rod domain⁷⁵ and/or the C-terminal tail domain that binds to core histones.^76,77

In addition to lamins, many lamin-binding proteins were shown to interact with DNA and/or chromosomal protein (Fig. 1). LBR interacts directly with DNA,^2278, and with human HP1-type chromodomain proteins,^79,80 which function as chromatin modifiers and regulators of gene expression and have been implicated in position effect variegation and heterochromatin organization.^81,82 In line with these findings, microinjected HP1 has been shown to localize transiently at the nuclear periphery in a deacetylation-dependent manner, before it translocates to intranuclear sites.⁸³ The association of HP1 with the nuclear envelope may be mediated by direct binding to LBR, but recent studies revealed a complex of LBR, HP1 and histones H3/H4, in which histones bind to both LBR and HP1 and mediate the LBR-HP1 interaction.⁸⁴ As the interaction of histones with HP1 was found to be affected by methylation of histone at lysine residue 9,^85,86 this could also provide a regulatory mechanisms for chromatin docking at the cellular periphery during cell proliferation and cell differentiation. In cross-linking studies LBR was also found to associate with chromatin-associated HA95, a nuclear protein with high homology to the nuclear A-kinase anchoring protein AKAP95.⁸⁷

LAP2 proteins contain several chromatin and/or DNA binding domains, which are either common to all or unique to some isoforms (Fig. 1). The constant N-terminal region, common to all LAP2 proteins, contains the LEM domain (amino acids 111-152), which was found by yeast two hybrid assay⁸⁸ and by biochemical studies⁸⁹ to interact with the chromosomal protein Barrier-to-Autointegration Factor (BAF), a protein that was first identified for its role in retroviral DNA integration.^90,91 Further studies revealed that BAF is a 89-residue protein that is highly conserved in multicellular eukaryotes⁹² and binds double-stranded DNA non-specifically forming nucleoprotein complexes (dodecamers) between DNA molecules.⁹³ Since the LEM domain is also present in emerin and MAN1,¹⁷ it can be expected that all these proteins interact with chromatin-associated BAF,⁹⁴ but this has not been experimentally tested yet.

Moreover, the N-terminal 50 residues of the LAP2 constant region were found by structural studies to contain a LEM-like motif that may bind DNA.³⁹ In accordance with these findings an N-terminal 85-residue LAP2 fragment was found to associate with chromosomes in vitro.³²

In addition to the N-terminal chromatin binding domains, common to all LAP2 proteins, in vitro studies revealed a DNA binding region in the LAP2β-specific C-terminus⁹⁵, and a region in LAP2α's unique C-terminus was found to mediate chromosome association of LAP2α (the chromosomal binding partner is still unknown). Several studies have indicated that the interaction of the LAP2 isoforms with chromatin, mediated by the different domains, is regulated in a very complex and interdependent manner. For example, LAP2α's unique C-terminal chromatin binding domain was found both essential and sufficient for interaction of the protein with chromosomes during post-mitotic nuclear assembly, while the N-terminal LEM-like and LEM domains were not required at this stage.⁹⁶ Furthermore, while LAP2 N-terminal fragments containing both the LEM-like and LEM motif did not interact with chromosomes when overexpressed in cells, and monomeric recombinant fragments did not bind to chromosomesin vitro,⁹⁶ GST fusion proteins of the same fragments, which form oligomeres, interacted with chromosomes.^96,32 This suggests that protein oligomerization, achieved by GST in the recombinant fragments or by C-terminal domains downstream of the LEM domain in full-length proteins, is required for tight interactions between the LEM domain and BAF and/or between the LEM-like motif and DNA. This hypothesis is further supported by recent in vitro binding studies showing that various Xenopus LAP2β-like isoforms, which are identical in their N-terminal part and contain the LEM domain, but differ slightly in their C-terminal regions, varied 9-fold in their affinities for BAF. Thus, the C-terminal unique regions in LAP2 isoforms may regulate the activity of the N-terminal LEM domain.⁸⁹ Aside from their diverse interactions with DNA and BAF, LAP2β has also been identified by cross-linking experiments to associate with HA95, similar to LBR.⁸⁷

It is not clear to what extent lamins and lamin binding proteins contribute to heterochromatin anchorage at the periphery. Considering the ˜ ten-fold larger abundance of lamins as compared to most lamin binding proteins, it can be assumed that lamins may have a major role in chromatin association. In line with this observation, it has been shown that the expression of a lamin mutant missing major parts of the rod domain caused relocalization of endogenous lamins and lamin-binding proteins to discrete patches at the nuclear envelope, not overlapping with patches of mutant protein. Despite the redistribution of lamin-binding proteins and pore complexes to patches of endogenous lamins, the position of chromatin was unchanged,⁹⁷ suggesting that lamins rather than lamin-binding proteins anchor chromatin at the periphery. However, since overexpression of lamin mutants caused major changes in nuclear shape and arrested cell growth, these effects may have been caused by the unphysiological conditions.

The large diversity of interactions of different lamin-binding proteins with DNA and with different chromosomal proteins argues for an important role of lamin-binding proteins in chromatin organization and anchorage at the NE. These interactions might be important for a “more specialized”, cell stage-specific regulation of the chromatin-NE link during cell differentiation and/or cell cycle progression.

Two recently described nuclear pore complex (NPC)-associated proteins might also link the peripheral lamina to the internal nucleoskeleton and mediate chromatin anchorage and organization. Tpr (translocated promoter region) is a constitutive component of filaments extending from the nuclear pore basket structure 100–350 nm into the nucleus⁹⁸ in extrachromosomal channel networks.⁹⁹ Apart from being involved in mRNA transport,^100,101 yeast Tpr homologues Mlp1 and Mlp2 have been shown to be involved in transcriptionally repressing telomeric genes by tethering telomere-binding factor yKu70 to the perinuclear region.¹⁰² The second candidate for a NPC-associated matrix protein is Nup153, which is a constituent of the nucleoplasmic pore basket^103-105 and has been implicated in nuclear import and export.^106-109 Highly sophisticated FRAP analysis and life cell imaging nicely showed that the nuclear lamina and NPC form a stable elastic network responsible for positioning NPCs in the membrane.¹¹⁰ Since Nup153 interacts directly with lamin LIII in Xenopus oocytes,¹¹¹ and NPCs assembled in the absence of Nup153 lack anchorage within the NE,¹¹² Nup153 may be important for linking the NPC to the lamina. Strikingly however, Nup153 fluorescence recovered much faster than those of other NPC proteins,¹¹⁰ indicating that Nup153 undergoes a rapid exchange between intranuclear and NPC-associated pools. In yeast, overexpression of Nup153 caused the formation of intranuclear membrane lamellae structures,¹¹³ suggesting that Nup153 might have additional nuclear binding partners. Zinc-finger motifs in Nup153 may mediate DNA interaction¹¹⁴ and early association of Nup153 with chromosomes after mitosis in a membrane-independent manner^110,115,116also suggests that the protein may interact with chromatin.

Potential Functions of Lamina Proteins in Interphase

The molecular and cellular functions of lamins and lamin complexes remain unclear, although functional disruption of lamins in Drosophila¹¹⁷ and C. elegans¹¹⁸ revealed that they are essential for viability. In mice targeted disruption of A-type lamins caused muscular dystrophy, loss of adipose tissue, and early death,⁴⁷ while mutations in the human lamin A gene were linked to inherited forms of muscular and lipodystrophies.^41,119-121

Similar to cytoplasmic intermediate filament networks, the nuclear lamina has been suggested to serve as the structural backbone for the nucleus defining nuclear shape.^2,11,119,120 Consistent with this function, nuclei assembled in vitro under lamin-depleted conditions were rather fragile^122,123 and nuclei of lamin A knockout mice showed a irregular shape.⁴⁷

The complex interactions of lamins and lamin-binding proteins with DNA and with chromatin-associated proteins (histones, HP1, HA95, and BAF) at the nuclear periphery (lamina including membrane proteins) and in the nuclear interior (A-type lamins and LAP2α) suggest functions of these proteins in higher order chromatin organization by providing specific chromatin docking sites at the NE and by structurally organizing chromatin fibers in the 3-dimensional nuclear space. Since higher order chromatin organization is ultimately linked to control of gene expression, lamina proteins might also be involved in this process. In line with this hypothesis, highly silenced human chromosome 18 occupies more peripheral territories in the nucleus as compared to highly active chromosome 19.¹²⁴ Furthermore, the lamina protein LBR is found in a complex with HP1 (see above), a protein involved in position effect variegation and control of gene expression.^81,82

In addition, components of the NE may directly influence transcription by interacting with transcription factors and/or chromatin remodeling complexes. A novel integral membrane protein of the inner membrane (Ring Finger Binding protein, RFBP), which resembles a type IV phospholipid pump, has recently been identified¹²⁵ and has been shown to directly interact with RUSH proteins, SWI/SNF transcription factors that model chromatin. Thus, association of chromatin with the NE may regulate transcriptional access directly¹¹⁹. Furthermore, several findings have indicated a direct interaction of lamina proteins with E2F transcriptional complexes, which regulate G1-S phase progression in cell cycle by activating transcription of S-phase specific genes.¹²⁶ The membrane-bound LAP2β was found by yeast two-hybrid analysis to bind mouse germ cell less (mGCL),¹²⁷ which in turn interacts with E2F-associated DP and regulates the cell cycle.¹²⁸ As overexpressed LAP2β reduced E2F-dependent reporter activity,¹²⁷ it is likely that LAP2β might negatively regulate E2F activity by tethering the transcription complex to the nuclear periphery, a mechanism known also for other transcription factors.² In addition, lamins A/C associate directly with the hypophosphorylated, active form of retinoblastoma protein (pRb),¹²⁹ which binds E2F and represses transcription of S-phase-specific genes.^130,131 LAP2α, which has been identified as a direct binding partner of A-type lamins³⁴ might be another functional component of such a complex.

Lamina proteins might also be involved in DNA replication. Nuclei assembled in the absence of lamin B3 in Xenopus in vitro nuclear assembly reactions were not able to replicate their DNA,^123,132 but addition of lamin B3 partially restored the phenotype.¹³³ Similarly, lamin mutants causing nuclear lamina disassembly were shown to inhibit DNA replication,^134-136 and lamin mutants causing a dramatic reorganization of the lamina and lobulated nuclei interfered with DNA replication and cell growth.⁹⁷ Interestingly, ectopic expression of lamin-binding LAP2β fragments in mammalian cells inhibited progression into S-phase,¹³⁷ while LAP2β mutants added to Xenopus in vitro nuclear assembly reactions influenced DNA replication positively.³⁰ Thus LAP2β might also be involved in DNA-replication either directly or indirectly by affecting lamina assembly.

Lamina proteins might also be involved in controlling apoptosis. In C. elegans, for instance, CED-4, a cell death activator, is translocated from mitochondria to the nuclear envelope before caspase activation,¹³⁸ suggesting that the lamina provides an attachment site for the apoptotic signaling machinery.² Lamins, LAP2α and LAP2β are early targets of apoptosis^139-141 and expression of uncleavable lamin mutants was shown to delay apoptosis for several hours.¹⁴¹ Furthermore, inhibition of lamin B assembly at the nuclear envelope upon preventing its postmitotic dephosphorylation induced apoptosis in human cells,¹⁴² suggesting that mislocalized lamins actively trigger apoptosis.¹⁴³

Interestingly, the Drosophila lamin Dm_o was recently found to be required for a cytoplasmic function in polarized cells, the outgrowth of cytoplasmic extensions from terminal cells of the tracheal system.¹⁴⁴ The molecular mechanisms however remain obscure.

These diverse functions of lamina/matrix proteins may explain how mutations in lamina proteins cause different inheritable human diseases affecting heart and skeletal muscle as well as adipose tissue (laminopathies).^41,119,121 It is conceivable that a disturbance of any of the above-described functions of lamins and lamin-binding proteins can contribute to the disease to different degrees. Mutations in emerin and lamin A do not only affect these two proteins but may have significant impact on other proteins tightly linked to lamin A structures. Thus, elucidating the function of any potential lamin A binding partner may provide important clues as to the molecular mechanisms of the disease. Therefore, in view of the recently reported interaction of LAP2α with the C-terminal region of A-type lamins³⁴ containing many lipodystrophy and EDMD-specific mutations,¹⁴⁵ it is intriguing to speculate that these mutations may effect LAP2α-lamin A interactions and interfere with LAP2α/lamin A functions. As such mutations would predominantly affect structures in the nuclear interior, the disease phenotype would be different from those caused by mutations in emerin or in lamin A, affecting mostly lamin A-emerin interactions and functions at the nuclear envelope.

Dynamics and Functions of Lamina-Chromatin Interactions During Mitosis

Multicellular eukaryotes reversibly disassemble the nuclear lamina, NPCs and the nucleoskeleton during mitosis, and the nuclear membrane merges into the endoplasmic reticulum.¹⁴⁶ This process is driven by phosphorylation of lamins, LBR, LAP1 and peripheral as well as intranuclear LAP2 proteins mostly involving mitotic cyclin-dependent kinases (cdk), although other kinases may also play a role.^10,31,66Mitotic A-type lamins are distributed in the cytoplasm probably as dimers or tetramers, while B-type lamins remain associated with membranes due to their C-terminal farnesyl modification, and probably also due to their interaction with LBR.²¹ LAP2β⁶ and LAP2α³³ dissociate from lamins and chromosomes in a mitotic phosphorylation-dependent manner. There are reported discrepancies depending on the cell systems used as to whether nuclear membrane proteins (LAP2β, LBR and emerin) and ER proteins segregate into distinct membrane structures during mitosis or whether both disperse throughout the endoplasmic reticulum.¹⁴⁷

Nuclear reassembly requires phosphatase activity and, at least for B-type lamins, has been shown to involve phosphatase PP1.¹⁴⁸ PP1 is targeted to the NE by the membrane-integrated A-kinase anchoring protein AKAP149, and this process was shown to correlate with the assembly of B-type lamins.¹⁴⁹ Inhibition of PP1 association with AKAP149 by a peptide containing the PP1 binding domain of AKAP149 resulted in lack of assembly of B-type lamins and apoptosis.¹⁴² Interestingly, however, assembly of A-type lamin was not effected by the peptide in HeLa cells, supporting other studies which show different pathways of assembly of A- and B-type lamins after mitosis.^34,58

Numerous studies have shown that the assembly of the NE and nuclear structure after cell division requires targeting and assembly of lamins and lamin binding proteins to chromosomes in a temporally and spatially regulated manner (Fig. 2). LAP2α appears to be the first protein among the lamina components to associate with chromosomes in anaphase, clearly before LAP2β-containing membranes accumulate and enclose the decondensing chromosomes.⁹⁶ Other membrane proteins, including LBR and emerin, accumulate at the chromosomal surface at the same time as LAP2β.^{115,116,150,151}Interestingly, initial association of LBR with chromosomes was shown to occur primarily at the peripheral chromosomal regions¹¹⁵, while LAP2β, emerin and lamins were enriched at more central regions of chromosomes closest to the spindle poles and the midbody.^{6,58,115,151,152}This suggested that association of LBR and LAP2β with chromosomes involves different mechanisms. Although a subfraction of B-type lamins might be targeted to the chromosomal surfaces by binding to LAP2β and or LBR and or histones, the bulk of lamin B assembly occurred after accumulation of the membrane proteins at the chromosomal surface.^6,58 There are clear differences in the assembly of B-type and A-type lamins. While lamin B1 assembled around chromosomes at anaphase-telophase transition following accumulation of membranes, A-type lamins were targeted to intranuclear sites much later when an intact continuous nuclear envelope had already formed.⁵⁸ Lamin A translocation to the nuclear interior might involve interaction with LAP2α³⁴ (see below).

Figure 2

Sequence of protein targeting to chromosomal surfaces during nuclear reassembly following chromatid separation, and responsible interactions. For details see text.

More recently, the dynamics of the NPC-associated proteins Nup153 and Tpr during mitosis have been tested. Interestingly, Nup153, but not Tpr, was recruited to chromosomes at the same time as LAP2β and LBR,^110,115,116 before accumulation of lamin B.⁵⁸ As this interaction is membrane-independent, it seems to be the first step of NPC assembly.

The mechanisms regulating the sequential association of lamina proteins with chromatin are not very well understood. It is particularly intriguing that LAP2α assembles prior to LAP2β, although both proteins contain the LEM and LEM-like motifs in their N-terminal constant regions, known to bind BAF and/or DNA (see above). Several recent observations might help to explain this phenomenon. It was shown that the association of LAP2α with chromosomes at early stages of assembly requires the a-specific C-terminal domain, which is absent in LAP2β.⁹⁶ The N-terminal BAF-binding domain, present in both LAP2α and b, did not interact with BAF at this stage of nuclear assembly, probably due to post-translational modification of LAP2 and/or BAF or due to an inhibitory effect of the C-terminal regions of LAP2.⁸⁹ Therefore, we favor the following model for the initial stages of assembly (Fig. 2). In phase 1 LAP2α associates with chromosomes via its C-terminus, not involving the N-terminal LEM and LEM-like domains. This association triggers conformational changes on the chromosomal surface and/or induces post-translational modification of BAF or other chromosomal proteins and allows binding of the LEM domain to BAF in phase 2. This mediates cross-linking of chromosomal territories by chromosome bound LAP2α, and targeting of LAP2β, and emerin, and thus membrane structures to the chromosomal surface (phase 3).

Despite the fairly detailed analysis of kinetics of chromosome association of various lamina proteins, their specific roles in nuclear assembly is still not clear. The reported contributions of lamins to NE assembly has been controversial.¹⁵³ While immunodepletion of lamins from in vitro Xenopus nuclear assembly extracts have indicated the formation of a NE in the absence of lamins,^122,123 other studies using Drosophila, mammalian and Xenopus extracts showed that immunoadsorbtion of lamins inhibited NE assembly.^154-156 As these different results were most likely caused by the different efficiencies in depleting and/or de-activating lamins by antibodies, Lopez-Soler et al have recently used a peptide containing the C-terminal domain of Xenopuslamin B3 in nuclear assembly reactions and found that the peptide inhibits nuclear lamin polymerization and also nuclear membrane assembly around chromatin.¹⁵⁷ Thus Xenopus lamin is likely to have important functions in NE assembly.

LAP2β has originally been implicated in targeting membranes to chromosomes⁶, but this has not been demonstrated directly. Microinjection of LAP2β's nucleoplasmic domain into mitotic cells did not inhibit nuclear membrane targeting and assembly but affected nuclear growth during G1-S phase progression.¹³⁷ The same fragment had similar effects, when added to Xenopus in vitro nuclear assembly reactions.³⁰ However, all these studies were performed in a background of endogenous LAP2 proteins. Interestingly, an N-terminal LAP2β fragment containing the BAF-binding region was able to inhibit nuclear membrane binding in the Xenopus assembly system,³⁰ but overexpression of the same fragment in mammalian cells had no detectable effect on cell cycle progression.⁹⁶ This suggests that different molecular mechanisms of nuclear assembly may exist in early embryonic versus somatic cell divisions. Apart from LAP2β, LBR has also been suggested to be involved in membrane-chromosome interactions in in vitro binding studies using LBR-immunodepleted membrane fractions.^158,159

The early accumulation of LAP2α around decondensing chromosomes suggested a function of the protein in providing a scaffold for chromatin organization. Considering the existence of at least two chromatin interaction domains in LAP2α, the protein is ideally suited to cross-link chromosomal regions and help to structurally organize chromatin in post-mitotic nuclei. Observations showing that overexpression of a C-terminal chromatin-binding fragment of LAP2α was toxic for the cells and that addition of the same fragment to mammalian in vitro nuclear assembly extracts inhibited NE formation⁹⁶ (Vlcek, Korbei and Foisner, submitted), supported this hypothesis, but the mechanisms remain obscure.

Conclusions and Future Prospects

The recent discovery of novel interaction partners for lamins and lamina-associated proteins have changed our view of how these proteins function in the cell nucleus. While former studies revealed mainly structural function, novel findings point towards important functions also in controlling DNA replication, gene transcription and cell cycle progression in a more direct fashion. Nevertheless, I believe that this is just the tip of the iceberg, and more interactions of lamin and lamin-binding proteins, which may be regulated in a development-, differentiation- or cell cycle-specific manner, will be identified in the future. This will give us a much clearer picture of the specific involvement of lamina proteins in these processes and will also allow to completely unravel the molecular mechanisms behind the lamin-related human diseases (laminopathies).

Acknowledgements

Work in the author's laboratory was supported by grants from the Austrian Science Research Fund (FWF) No. P13374 to RF.

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