Nuclear Envelope: History
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Subjects: Agriculture, Dairy & Animal Science | Allergy
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Maria Alvarado-Kristensson

The formation of the nuclear envelope and the subsequent compartmentalization of the genome is a defining feature of eukaryotes. Traditionally, the nuclear envelope was purely viewed as a physical barrier to preserve genetic material in eukaryotic cells.

  • nucleus
  • envelope
  • cell cycle

1. The Nuclear Envelope in Cell Division

Cancer is the result of uncontrolled cell division. NE proteins can mostly affect the cell cycle in higher eukaryotes when the cells undergo open mitosis and the nucleus architecture is dismantled to allow the partitioning of the genetic material between the daughter cells. Indeed, the finding in mammalian cells of the depolymerization of lamin polymers upon hyperphosphorylation of lamin A at the onset of mitosis was the first clue in NE regulating cell division [1][2][3][4].

1.1. Nuclear Envelope Disassembly at the Onset of Cell Division

Phosphorylation of NE proteins and of their binding partners drives the coordinated disruption of NE interactions and structures at the beginning of mitosis. Together with lamins, several NPC proteins and NETs are also phosphorylated by mitotic kinases (gp210, LAP2β, and lamin B receptor –LBR), as shown in human, murine, or avian models [5][6][7][8]. In human and Caenorhabditis elegans cells, the same occurs with barrier-to-autointegration-factor (BAF), a chromatin binding partner of several NETs connecting chromatin to NE [9][10] (reviewed in [11]).
Disassembly of the NE needs close coordination with the generation of the bipolar mitotic spindle. In prophase, NPC-attached dynein motors assist in the separation of the centrosomes [12][13].
Disassembly of NPCs is not a straight reversal of the assembly steps (reviewed in [14][15]). In many cases, components of the NE and NPCs actively participate in mitotic events when released from their interphase organization [16]. At the G2/M cell cycle transition, two nucleoporins participate in tethering centrosomes to the NE [17][18]. During prophase, these interactions might help microtubules in their function for NE breakdown [19] and for moving of sister centrosomes to opposite sides of the nucleus [17][18][20]. At the end of prophase, the NPC is dismantled releasing elements with important regulatory functions during mitosis: NUP358 at kinetochore functioning [21][22][23], NUP88 and other nucleoporins interfering with microtubule dynamics to promote spindle assembly, NUP98 in regulating the adenomatous polyposis coli (APC)/C [16][24][25][26] (reviewed in [14]).
During mitosis in animal cells, remodeled nuclear membranes intermix in a large part with the tubulo-vesicular mitotic ER [27], while NE vesiculation also occurs [28][29][30][31][32][33][34][35]. Regarding the over 100 different NETs in any given cell, several of them go into a storage form and others exert critical functions, such as RanGTP, the transport receptor importin/karyopherinβ, and RepoMan ([36], reviewed in Ref. [37][38][39]).
Several features of cancer cells, such as lagging chromosomes, aneuploidy, and polyploidy, might occur after a failed NE breakdown at the onset of mitosis and the subsequent blocking of spindle assembly.

1.2. Nuclear Assembly After Cell Division

1.2.1. Chromatin Enclosing, INM Protein Recruitment, and NPC Formation

During metazoan anaphase, chromosomes cluster compactly together in a disc-like configuration whose surface drives nuclear assembly. During early telophase, NE reassembly is initiated by changes at this chromatin surface (i.e., removal of mitotic histone marks by phosphatases) and the dephosphorylation-induced binding of NETs and their associated membranes to chromatin (reviewed in [27]).
Several mechanisms combine to recruit ONM and INM proteins, constituents of NPCs, and lamins. In metazoa, INM proteins are attracted both by both specific interactions and by the general affinity of many INM proteins for chromatin/DNA, for example, LBR binds heterochromatin protein 1 (HP1) [40][41] and histone H3 [42][43][44]. Importantly, NET and NPC binding to mitotic chromosomes in early telophase seems to drive NE reassembly [45][46][47][48][49], implicating phenylalanine and glycine (FG)-rich nucleoporins and the AT-hook-domain containing protein, ELYS/Mel-28 (Figure 1). ELYS localizes not only to NPCs, but is also associated with chromosomal kinetochores during cell division. At the end of mitosis, ELYS recruits the NUP107-160 subcomplex, which is required for the correct segregation of mitotic chromosomes [50][51]. In addition, in NPC assembly and chromatin decondensation, lysine demethylase LSD1 is required [52], while the Repo-Man-promoted dephosphorylation of histone H3 seems indispensable for targeting importin-b to mitotic chromatin [53] (Figure 1).
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Figure 1. A model for the role of nuclear γ-tubulin in chromatin enclosing, inner nuclear membrane (INM) protein recruitment, and nuclear pore complex (NPC) formation in nuclear disassembly and reassembly upon cell division. (a) Schematic representation of the nucleus and nuclear envelope (NE) during interphase and subsequent mitosis. Post-mitotic reassembly of the NE is initiated by changes at the chromatin surface (i.e., removal of mitotic histone marks by phosphatases) and dephosphorylation-induced binding of nuclear envelope transmembrane proteins (NETs) and their associated membranes to chromatin. Engulfment of recently separated sister chromatids by the NE occurs via deposits of membrane fragments on the chromatin surface that trigger the enveloping process. The NE is reformed from endoplasmic reticulum (ER) membranes, which contact chromatin either as tubules or sheets. After membrane deposition, NPC assembly allows importation of the elements for nuclear lamina assembly. Microtubule organizer γ-tubulin plays a distinct role in promoting this NE formation by providing a γ-tubulin boundary indispensable for NE assembly. At the onset of mitosis, the lamina meshwork is disrupted, but the γ-tubulin boundary around the mitotic chromosomes is maintained. During mitosis, chromatin-associated γ-strings link the sister chromatids to the cytosolic γ-string pool. Finally, at anaphase/telophase, the γ-tubulin boundary composed of cytosolic and chromatin-associated γ-strings forms a supporting scaffold that assists the formation of the nuclear envelope. (b) Magnified boxed area of NE at interphase: During interphase, γ-tubulin bridges connect the cytosolic and the nuclear γ-tubulin pools ([54], reviewed in [55][56]). The LINC protein nesprins recruit centrosomal proteins and regulate the nucleation of microtubules from the NE in myotubes [57]. The INM protein Samp1 is in contact with both γ-tubulin and SUN1 [58]. At the beginning of mitosis, during the rupture of the NE to the spindle microtubules, Samp1 might recruit γ-tubulin from the fenestrated NE. In the spindle, γ-tubulin and Samp1 complex together with augmins would potentially assist in the nucleation of the microtubules. Not to scale.
Engulfment of recently separated sister chromatids by the NE occurs in an astonishingly short timeframe thanks to deposits of membrane fragments on the chromatin surface that trigger the enveloping process (reviewed in [27][59]). It is still a matter of debate whether ER moves toward chromatin in the way of membrane sheets or tubules (reviewed in [60]). Regardless of the case, defects in any of these mitotic functions could affect the quality of cell division and lead to aneuploidy, a common feature of tumors [61]. In the metazoa, NPC formation occurs in two different phases of the cell cycle and through different assembly mechanisms: Post-mitotic NPC assembly and interphase NPC formation [62][63][64][65][66]. Two models for post-mitotic NPC assembly have been proposed: The insertion model claims that NPCs are reassembled into an intact nuclear envelope, while the enclosure model proposes that NPC assembly starts before the NE encloses the chromatin (reviewed in [67][68][69]). In any case, post-mitotic NPC assembly happens in a step-wise manner and it is subjected to fine surveillance mechanisms (reviewed in [14]). NPC assembly begins in early anaphase with soluble NPC proteins (Nup107-160 scaffold) positioning on the chromatin, mediated by Elys/Mel28, before membrane reformation. Then, it might be followed by the recruitment of transmembrane nucleoporins (reviewed in [70][64][65]). In the case of NUP153, it might even participate in the biogenesis of the lamina [71].
Surveillance mechanisms ensure correct post-mitotic reformation of NPCs (reviewed in [14]) and the assembly of the basket-like feature is particularly necessary to complete cytokinesis in a timely manner [71]. Aurora kinase B links the basket-like feature with cytokinesis, and this is currently explored as a chemotherapeutic approach in clinical trials against cancer [72].
The number of NPCs formed during interphase doubles prior re-entry into mitosis (reviewed in [67]). However, little is known about NPC formation during interphase, although it is differentially regulated compared to post-mitotic NPC assembly. Interphase NPC formation is dependent upon cyclin-dependent kinase (CDK) activity, but not upon ELYS/Mel-28 [73][74].
Kinetochores and microtubules are also essential in NE reassembly, particularly, in the recruitment of BAF to the chromatin template [75]. Acetylated Lem4 (ANKLE2) participates in this process by promoting the dephosphorylation of BAF [46][47][76]. The binding of BAF to chromatin is indispensable for most of the integral-membrane LEM-domain containing proteins to connect to chromatin through their interaction with BAF itself [75][77][78]. A recent elegant report using human cells showed that the role of BAF in nuclear assembly depends upon its ability to link distant DNA sites [79]. Microtubule organizer γ-tubulin may play a noncanonical and distinct role in promoting NE assembly [54]. A local suppression of microtubules during nuclear formation, fulfilled by chromatin-bound microtubule regulators, is required in X. laevis for proper pronuclear assembly and regular morphology of the nucleus [80]. An association of γ-tubulin with the nucleoporin ELYS/Mel-28 and the NE reassembling GTPase, Ran, has been described in X. laevis [81]. In both X. laevis and mammalian cells, a γ-tubulin boundary made of γ-strings is formed around chromatin during NE assembly, and this γ-tubulin boundary ensures the formation of the lamina around chromatin by recruiting of lamin B (Figure 1) [54]. The formation of fibrillar aggregates of γ-tubulin was further confirmed upon chaperonin containing TCP-1 (CCT) action in vitro [82]. Shaping the nucleus and achieving a regular distribution of NPCs has been shown to depend upon the γ-tubulin complex protein 3-interacting proteins in Arabidopsis thaliana [83]. Furthermore, in human cells, expression of a γ-tubulin mutant that lacks the DNA-binding domain forms chromatin-empty nuclear-like structures, demonstrating that a persistent interplay between the chromatin-associated and the cytosolic pools of γ-tubulin is required for proper NE assembly [54].
The finding that several NETs (NET5/Samp1/Tmem201, WFS1, Tmem214, and otefin) partially concentrate on or around the mitotic spindle, and in the case of the latter, the centrosome during mitosis together with the tissue specificity of many of the NETs affecting the cell cycle, suggests that further implications of these proteins in mitosis might come in the future (reviewed in [84]).

1.2.2. Spatial Distribution of NE Elements

Chromatin discs involve different areas: the “inner core” (the central region of the disc that faces the midzone), the “outer core” (the central region that faces away), and the “non-core” region (the peripheral edge of the disc) [85][75][86][87].
In metazoa, INM proteins and membrane destined for the NE make initial contacts at the non-core region with the γ-tubulin boundary before spreading around and engulfing chromatin [54][88]. Telomeric regions of sister chromatids are bound with unique proteins essential to nuclear architecture, as is LAP2α [48][49]. Furthermore, in newly forming nuclei, telomeres localize to the periphery of the nucleus, suggesting that these regions are involved in the initial seed of nuclear assembly [89].
The core region (inner and outer) is the target for ESCRT (endosomal sorting complexes required for transport) pathway proteins to recruit the microtubule severing factor spastin and seal annular gaps in the newly formed NE [90][91][92][93]. This core is initially deficient in NPC formation, but the process begins at this site soon after membrane closure [87].
The relevance of NPCs in anchoring interactions necessary for nuclear shape maintenance and structural integrity is illustrated, first, by interactions between nucleoporins NUP53, NUP88 and NUP153 and lamins [94][95][96], second, by the finding of polymorphic, lobular nuclear shapes after the depletions of these nucleoporins [94][97][98], and third, by SUN domain-containing protein 1 (SUN1) preferential location in the vicinity of NPCs [99].
All in all, defects in NE proteins might cause an inability to disassemble the NE at mitosis onset (generating partially maintained connections between NE fragments and chromatin) and to reassemble NE at the end of mitosis, blocking proper chromosome segregation and resulting in micronuclei and aneuploidy [61]. The wrapping of all chromosomes into a sole nucleus is thus essential for preserving the integrity of the genome and preventing the development of tumors.

2. The Nuclear Envelope in Cell Cycle Regulation and Signaling

2.1. Nuclear Envelope in Cell Cycle Regulation

Several elements of the NE (lamin A, lamin B, LAP2α, γ-tubulin, and emerin) have been shown to interfere with the function of the main effectors of cell cycle regulation (retinoblastoma protein–RB, E2Fs, c-Myc), as reviewed below.
In the mammalian cell cycle, normal cells exert a tight regulation of the G1-to-S phase transition, whereas in cancer cells, this transition is a main objective for dysregulation. RB is one of the earlier identified tumor suppressors [100]. Hence, RB activity is deregulated in a broad spectrum of tumors [101]. RB has abundant binding partners [102], the most important of which is the transcriptional factor E2F, which controls a range of genes important for entry into the S phase of the cell cycle. Hypophosphorylated RB binds to E2F complexes and represses the expression of S-phase genes, retaining cells in G1. CDK-dependent phosphorylation promotes the release of RB from E2F and cell cycle progression [103].
In mammals, lamin A regulates G1-to-S phase transition by affecting the RB pathway [104][105][106][107][108], since A-type lamins are required for proper RB function. In detail, A-type lamins promote RB-dependent transcriptional repression of E2F target genes. Furthermore, A-type lamins influence three other machineries regulating RB function: RB phosphorylation, RB localization, and RB protein stability [109][110]. The effect of A-type lamins in RB protein stability, together with the altered activity of ubiquitin ligase components detected in cells expressing mutant forms of lamin A, raise the possibility that A-type lamins work as coordinators of nuclear proteasome function [111].
The RB pathway is further implicated in telomere regulation and cell senescence and cell differentiation in multiple lineage, DNA replication, mitosis, and DNA-damage-activated checkpoint pathways (among others) [101], further linking A-type lamins to all of these processes. Supporting the implication of lamins in the regulation of DNA replication, intranuclear A-type lamins have been shown to associate with initial sites of DNA synthesis upon S-phase entry [112]. In immortalized cells, lamin B was localized to intranuclear sites of late S-phase replication [113], and disruption of the lamin structure impairs initiation of DNA synthesis [114][115][116].
More than A-type lamins, nuclear γ-tubulin also regulate the transcriptional activity of E2F [117]. Nuclear γ-tubulin and E2F concur in a DNA-binding complex isolated from E2F-regulated promoters [117]. In addition, RB1 and γ-tubulin proteins mutually control their expression, and, in several tumors, an inverse correlation in their expression levels was reported for γ-tubulin and RB1 [118]. Interestingly, γ-tubulin also interacts with lamin B recruitment at post-mitotic NE reassembly, as previously mentioned [54].
Other A-type lamin functions may promote G1 maintenance, since RB–lamin A/C and extracellular signal-regulated kinase (ERK)1/2–lamin A/C complexes are mutually exclusive. When G1 arrested cells are stimulated with serum, c-Fos protein is phosphorylated by mitogen activated protein kinase (MAPK) ERK1/2. Phosphorylated c-Fos associates with c-Jun- to form a dimeric Activating Protein 1 (AP-1) transcription activator complex that mediates cell cycle progression [119]. ERK1/2-dependent lamin A/C binding upon serum stimulation releases RB from the RB–lamin A/C complex, thereby promoting cell cycle progression.
The NPC-associated sentrin-specific protease 1 (SENP1) is also reported to influence cell cycle progression by regulating the expression of CDK inhibitors [120][121].
Regarding c-Myc-encoded proteins, their association with the nuclear matrix was first described in avian nuclei [122], and more recently, it was shown that the stabilized and active form of the MYC protein (pS62MYC) is enriched at the nuclear periphery of mammalian cell lines in proximity with lamin A/C [123], and precisely localizes to the nuclear pore basket [124]. However, how this regulates transcription and cellular functions remains to be elucidated.
Concerning cell senescence, the NE and the RB pathway have been implicated in an oncogenic signaling that triggers a cell cycle arrest program, i.e., oncogene-induced senescence (OIS). A dramatic reorganization of heterochromatin occurs in OIS. OIS cells lose heterochromatin interactions with lamin B1 through lamina-associated domains (LADs) [125][126], therefore, heterochromatin leaves the nuclear periphery and appears as internal senescence-associated heterochromatin foci (SAHFs) [127]. The activation of the pRB pathway is implicated in the appearance of SAHFs [127], while the NE is also implicated via laminB1 and LBR [128][129] and nuclear pore density [130]. In addition, the composition and density of the NPC changes during differentiation and tumorigenesis [131][132][130][133][134].
With respect to the maintenance of telomere metabolism [135] and DNA damage, in human cells, mutant LMNA has been connected to p53 engagement due to enhanced DNA damage (reviewed in [136]). Indeed, retinoblastoma independent regulation of cell proliferation and senescence by the p53-p21 axis was reported in lamin A/C-depleted cells [137].
In apoptosis, both via the intrinsic and extrinsic pathways, lamins have been described as cleaved by caspases 3 and 6. Indeed, the cleavage of lamin proteins by caspases is a necessary step in apoptosis that allows for nuclear membrane degradation to proceed, followed by chromatin condensation in a murine model [138]. In human and avian cells, A-type lamins are cleaved at their conserved VEID site by caspase 6, while B-type are cleaved at their VEVD site by caspase 3 [139][140][141]. In contrast, an active role of lamins in the induction, but also the prevention of apoptosis is beginning to emerge (reviewed in [142]). In cancer, apoptosis is usually reported. Strikingly, apoptosis levels are increased in the most highly proliferative tumors compared to lowly proliferative tumors. The role of lamins, if any, behind these altered levels is still unclear. One possibility would be that the amount of lamins present and the accessibility of lamins for caspases could delay the onset of apoptosis in certain tumors [143].
In metazoan, an estimated 10% of total A-type lamins localize throughout the nucleoplasm in a mobile and dynamic pool, most likely in association with LAP2α [48][116][144]. Studies on the role of A-type lamins and the RB pathway do not discriminate between these two lamin pools. However, the LAP2α promoter was reported to bind E2F1 and c-Myc [14], E2F1 and E2F4 [15], E2F3b [16], and E2F7 [17], as assessed by chromatin immunoprecipitation and microarray techniques. Indeed, LAP2α expression aligns with the phase of the cell cycle, and its overexpression has been described in various human tumor samples and cancer-derived cell lines (reviewed in [145]).
A last example is the INM protein emerin, which has been linked to cell cycle misregulation in microarray studies in X-linked EDMD patient samples where the lack of emerin disrupts the RB pathway [146].
In summary, several elements of the NE interact with the regulators of cell cycle progression, cell senescence, telomer metabolism and apoptosis. Therefore, perturbations in NE elements affecting the strict control of these interactions can lead to the development of cancer.

2.2. Nuclear Envelope in Cell Signaling

Extracellular or cytoplasmic stimuli reach the nuclear interior through signal transduction with the aim of inducing a cellular response, resolved mainly through variations in gene expression. The following signaling cascades from the plasma membrane count with an additional layer of regulation at the NE: MAPK signaling, AKT-Mammalian Target of Rapamycin signaling, Notch signaling, Wnt signaling, NF-κB signaling, and transforming growth factor-β (TGFβ) signaling. This control comes from the fact that signaling cascades need to get into the nucleus through the NPCs and that several effectors (β-catenin and smads) are sequestered at the NE by multiple NETs, as described below.

2.2.1. Lamins in Cell Signaling

The MAPK pathway dysregulation has been shown to be a driving factor in oncogenesis [147][148][149]. This pathway involves three main arms: ERK1/2, c-Jun NH2-terminal kinase (JNK), and p38 [150][151]. Phosphorylated MAPKs transit to specific subcellular compartments, such as the nucleus, to elicit their function. The localization of phosphorylated MAPKs to the nucleus is predominantly mediated by binding interactions with sequestering anchors and components of the nuclear transport machinery. In the nucleus, phosphorylated MAPKs regulate various cellular processes from growth to apoptosis, passing through differentiation, inflammation, metabolism, stress response, and autophagy [150][151][152]. An ERK1/2-activated transcription factor promoting cell cycle progression is, as previously introduced, c-Fos. c-Fos activity is suppressed by a sequestering interaction with lamin A that localizes this transcription factor to the NE [153]. Furthermore, ERK1/2 colocalizes with c-Fos at the NE by means of binding lamin A and this leads to the phosphorylation and release of c-Fos from the NE in mammalian models [154]. In addition, enhanced nuclear accumulation of ERK1/2 and JNK was reported in mice carrying a missense mutation that causes autosomal dominant EDMD in humans [155].
The AKT- mammalian target of rapamycin (mTOR) signaling pathway is frequently co-activated along with ERK1/2 in response to growth factor signaling and in various forms of cancer [156][157]. Alterations in A-type lamins have been shown to trigger AKT-mTOR signaling in the above-mentioned mice model of autosomal dominant EDMD and in mice expressing a truncated form of lamin A (lamin AΔ8-11). In mammals, lamin A itself can be phosphorylated by AKT, by which its expression can be regulated [158][159].
Hutchinson–Gilford progeria syndrome (HGPS) is mainly linked to a silent mutation LMNA. This G608G mutation in LMNA triggers a cryptic splice site and as a result, the progerin protein is produced. Progerin is a truncated form of prelamin A where the last C-terminal 50 amino acids are missing [160][161]. Several signaling pathways are imbalanced in HPGS due to the presence of progerin:
  • One of them is Notch signaling, which is altered in many cancers and is thought to maintain cancer stem cells [162]. This highly conserved juxtacrine signaling is involved in regulating cell fate specification and it is altered in the mesenchymal stem cell lineage in HPGS.
  • Additionally, the deposition of extracellular matrix (ECM) is altered in children with HGPS, mainly due to the reduced activity of the TCF4/LEF1 complex, a key downstream effector of the Wnt signaling pathway. Progerin expression decreases the expression and nuclear accumulation of LEF1 [163].
  • NF-κB signaling functions as a sensor for genotoxic stress [164] and LmnaG609G/G609G mice (murine equivalent of LMNAG608G/G608G mutation) exhibit activated NF-κB signaling through ATM-NEMO-mediated mechanisms [165].

2.2.2. LEM Proteins in Cell Signaling

Several LEM proteins have been shown to recruit and regulate the transcriptional co-activators of the Wnt and the TGFβ signaling pathways: β-catenin and Smads, respectively:
  • Emerin is a binding partner of β-catenin. Upon activation of Wnt signaling, β-catenin escapes proteasomal degradation and accumulates in the nucleus. Emerin binding to β-catenin inhibits its activity by facilitating nuclear export, thereby preventing accumulation in the nucleus in human fibroblasts [166].
  • MAN1 binds to receptor-mediated Smads (rSmads), intracellular mediators of the TGF-β, and bone morphogenic protein (BMP) signaling. rSmads play an intimate role in cancer metastasis [167]. The C-terminus of MAN1 sequesters rSmads at the inner nuclear membrane, thereby preventing their ability to migrate to gene enhancer regions and activate transcription [168][169][170].
In brief, several elements of the NE provide an additional stage of regulation of signaling pathways that control proliferation and, in turn, potential points whose dysregulation may generate the unrestrained proliferation typical of tumor transformation.

This entry is adapted from the peer-reviewed paper 10.3390/ijms20102586

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