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Nuclear envelope

The nucleus was first described by Robert Brown in 1831, with its surrounding double lipid bilayer, known as the nuclear envelope, visualized using electron microscopy in the mid-1950s.^[1] The nuclear envelope encloses the nucleus in eukaryotic cells, serving as a selective barrier that separates the genetic material and nucleoplasm from the cytoplasm while facilitating controlled exchange of molecules.^[2] It consists of an inner nuclear membrane (INM) facing the nucleoplasm and an outer nuclear membrane (ONM) continuous with the endoplasmic reticulum, with the two layers fused at sites of nuclear pore complexes (NPCs) and separated by a narrow perinuclear space of approximately 30–50 nm.^[3] This structure provides mechanical stability to the nucleus and supports essential cellular processes, including the organization of chromatin and the regulation of gene expression.^[4] Key components of the nuclear envelope include the nuclear lamina, a dense meshwork of intermediate filament proteins known as lamins (primarily A-type and B-type in metazoans), which underlies the INM and anchors chromatin, transcription factors, and other nuclear proteins to maintain nuclear architecture.^[3] Embedded within the envelope are NPCs, massive protein assemblies composed of around 30 distinct nucleoporins forming octagonal channels with an outer diameter of about 100 nm and a central transport pore of roughly 40 nm, numbering 3,000–4,000 per nucleus in vertebrate cells.^[4] Additional elements, such as integral membrane proteins (e.g., LEM-domain proteins like LAP2, emerin, and MAN1 on the INM) and linker of nucleoskeleton and cytoskeleton (LINC) complex components (e.g., SUN and KASH proteins spanning the membranes), connect the envelope to both chromatin and the cytoplasmic cytoskeleton.^[2] The primary functions of the nuclear envelope encompass nucleocytoplasmic transport, where NPCs enable passive diffusion of small molecules (<40–60 kDa) and active, energy-dependent translocation of larger macromolecules like proteins and RNAs via receptor-mediated mechanisms involving Ran GTPase.^[5] Beyond transport, it contributes to genome protection by shielding DNA from cytoplasmic threats, influences gene regulation through interactions with chromatin at the nuclear periphery (e.g., heterochromatin tethering), and participates in mechanosensing by transmitting mechanical forces from the cytoskeleton to modulate nuclear shape and function.^[2] The envelope is highly dynamic, undergoing disassembly during mitosis in open-mitosis organisms and reassembly afterward, with recent studies highlighting roles for ESCRT-III machinery in repairing ruptures and maintaining integrity under stress.^[4]

Overview

Definition and basic components

The nuclear envelope is a double lipid bilayer that encloses the nucleus in eukaryotic cells, consisting of an outer nuclear membrane and an inner nuclear membrane that together separate the nuclear contents from the surrounding cytoplasm.^[3]^[6] This structure forms a selective barrier that protects the genetic material within the nucleus while facilitating controlled exchange of molecules between the nucleoplasm and cytoplasm.^[4]^[3] Key associated structures include nuclear pore complexes, which span the double membrane to enable transport, and the nuclear lamina, a meshwork that provides mechanical support to the inner membrane.^[4]^[7] The nuclear envelope is a hallmark of eukaryotic cells, where it enables compartmentalization of cellular processes; it is absent in prokaryotes, which lack a membrane-bound nucleus.^[8]^[9]

Historical context and discovery

The earliest observations of the cell nucleus, including hints of its surrounding envelope, date back to the advent of microscopy in the late 17th and early 18th centuries. In 1710, Dutch microscopist Antoni van Leeuwenhoek reported seeing a distinct structure within amphibian and avian erythrocytes using his single-lens microscope, which is now recognized as the nucleus, though he did not fully describe its membranous boundary.^[1] Subsequent light microscopy efforts in the 18th century, such as Felice Fontana's 1781 description of a central body in eel skin cells, built on this but remained limited by resolution.^[1] Advancements in the 19th century provided clearer insights into the nucleus and its envelope through improved optics and systematic botanical studies. In 1831, Scottish botanist Robert Brown observed a dense, opaque structure in the cells of orchids and other plants during his investigations of fertilization mechanisms, coining the term "nucleus" to describe it and noting its consistent presence across plant species.^[10] Eduard Strasburger, a German cytologist, further detailed nuclear structures in plant cells during the 1880s, describing the nucleus's role in division in works on mitosis, contributing to the emerging cell theory.^[11] These light microscopy observations established the nucleus as a universal cellular feature but could not resolve its fine architecture. The double-membrane nature of the nuclear envelope was confirmed in the 1950s with the advent of electron microscopy. In 1950, H.G. Callan and S.G. Tomlin used electron micrographs of amphibian oocyte nuclei to reveal a porous outer layer and continuous inner layer, marking the first visualization of nuclear pores.^[12] Shortly after, in 1954, M.L. Watson's electron microscopy of mammalian cells demonstrated pores in the nuclear membrane and its continuity with the endoplasmic reticulum, solidifying the envelope's bipartite structure.^[13] Studies in the 1960s and 1970s elucidated the nuclear envelope's dynamic behavior during mitosis, showing its disassembly to facilitate chromosome segregation. Ultrastructural analyses using electron microscopy revealed that the envelope disassembles during prophase, with nuclear pore complexes breaking down to allow spindle access to chromatin. Further work in the 1970s, including electron microscopic tracking of envelope reformation in telophase, highlighted phosphorylation-driven breakdown and dephosphorylation-mediated reassembly, establishing its essential role in cell division.^[14]

Structure

Outer nuclear membrane

The outer nuclear membrane (ONM) forms the cytoplasmic-facing layer of the nuclear envelope and is directly continuous with the rough endoplasmic reticulum (ER), allowing the perinuclear space to connect seamlessly with the ER lumen.^[3] This continuity enables the ONM to participate in ER-associated functions, including the binding of ribosomes on its cytoplasmic surface, which facilitates the synthesis of transmembrane and secreted proteins.^[3] In many cell types, these ribosomes stud the ONM, mirroring the rough ER's role in protein translation.^[3] The ONM is a phospholipid bilayer, primarily composed of glycerophospholipids such as phosphatidylcholine (PC) and phosphatidylethanolamine (PE), with low levels of cholesterol compared to the plasma membrane.^[15] This lipid profile, enriched in polyunsaturated fatty acids, supports the membrane's fluidity and curvature while resembling that of the ER due to their shared continuity.^[16] The bilayer measures approximately 10 nm in thickness, contributing to the overall structural integrity of the nuclear envelope.^[17] Key integral membrane proteins associated with the ONM include the nesprin family, which span the membrane and extend into the cytoplasm to link the nucleus to the cytoskeleton.^[18] Nesprins, such as nesprin-1, -2, and -3, interact with actin filaments via nesprin-1 and -2, and with intermediate filaments through nesprin-3, thereby anchoring the nucleus and providing mechanical stability against cytoskeletal forces.^[19] This linkage is essential for maintaining nuclear positioning and shape during cellular processes involving mechanical stress.^[18]

Inner nuclear membrane

The inner nuclear membrane (INM) forms the nucleoplasm-facing layer of the nuclear envelope, directly interfacing with the nuclear lamina and chromatin to maintain nuclear architecture and facilitate specific molecular interactions. Unlike the outer nuclear membrane, the INM hosts a specialized proteome of integral membrane proteins that anchor nuclear components and contribute to genome organization. These proteins are targeted to the INM through diffusion-retention mechanisms involving binding to nuclear lamina or chromatin after initial insertion into the endoplasmic reticulum.^[20] Key integral membrane proteins of the INM include lamina-associated polypeptides (LAPs), such as LAP1 and LAP2, as well as emerin, which collectively define the INM's functional identity. LAPs and emerin possess the LEM domain, a conserved structural motif approximately 40 amino acids long that forms a helix-turn-helix structure critical for protein-protein interactions.^[21] This domain enables binding to barrier-to-autointegration factor (BAF), a DNA-bridging protein that links the INM to chromatin. Other LEM-domain proteins, like MAN1, further diversify these interactions, supporting post-mitotic nuclear reassembly and chromatin tethering.^[21]^[22] Through LEM-domain proteins, the INM serves as an anchoring site for heterochromatin, promoting the peripheral localization of lamina-associated domains (LADs) that repress gene expression. BAF-mediated binding recruits heterochromatin to the INM, influencing chromosome architecture and facilitating epigenetic silencing in these regions.^[23] The INM's lipid bilayer, approximately 4-10 nm thick and similar to the outer nuclear membrane, exhibits curvature that conforms to the nucleus's irregular shape, shaped by underlying structures like the nuclear lamina.^[24] INM-chromatin and INM-lamina interactions enhance nuclear mechanical properties, contributing to overall nuclear stiffness and proper positioning within the cytoplasm. Tethering of chromatin to the INM via these proteins resists deformation, with nuclei depleted of such tethers showing significantly reduced stiffness under mechanical stress. The nuclear lamina, a thin meshwork underlying the INM, amplifies this support by distributing forces across the nuclear surface.^[25]

Perinuclear space and nuclear lamina

The perinuclear space is a narrow, fluid-filled lumen situated between the inner and outer nuclear membranes of the nuclear envelope, typically measuring 30-50 nm in width. This space is continuous with the lumen of the endoplasmic reticulum, allowing for the exchange of ions, small molecules, and certain proteins that participate in cellular signaling and homeostasis. The perinuclear space serves as a dynamic compartment that maintains the spatial separation between the two membranes while facilitating limited molecular diffusion, contributing to the overall integrity of the nuclear barrier.^[26]^[27]^[28] Beneath the inner nuclear membrane lies the nuclear lamina, a dense meshwork of intermediate filaments that provides essential structural support to the nucleus. Composed primarily of lamin proteins classified as type V intermediate filaments, the lamina includes A-type lamins (lamins A and C, which are splice variants derived from the LMNA gene) and B-type lamins (lamins B1 and B2, encoded by LMNB1 and LMNB2 genes, respectively). These lamins assemble into a filamentous network through head-to-tail polymerization and lateral associations, forming a resilient scaffold approximately 30-100 nm thick that lines the nucleoplasmic side of the inner membrane. The lamina's structure is stabilized by interactions with inner nuclear membrane proteins, such as LAP2, emerin, and MAN1, which anchor it to the membrane.^[29]^[30]^[31] The nuclear lamina plays critical roles in maintaining nuclear integrity by conferring mechanical stability and resistance to physical stress, enabling the nucleus to withstand cytoskeletal forces during cellular movement and deformation. It also anchors chromatin domains, particularly lamina-associated domains (LADs), to the nuclear periphery, thereby influencing chromatin organization and gene expression regulation. Lamin proteins contain specific phosphorylation sites, primarily in their N- and C-terminal regions, which are targeted by kinases like CDK1 during mitosis to trigger lamina disassembly, allowing for nuclear envelope breakdown. In interphase, dephosphorylation restores the meshwork, ensuring nuclear reformation and structural recovery. These functions highlight the lamina's dual role as a supportive framework and a regulator of nuclear architecture.^[32]^[33]^[34]^[35]

Nuclear pore complexes

The nuclear pore complex (NPC) is a massive macromolecular assembly that spans both membranes of the nuclear envelope, serving as the primary conduit for molecular exchange between the cytoplasm and nucleus. In eukaryotic cells, each NPC exhibits eightfold rotational symmetry and is composed of approximately 30 distinct proteins known as nucleoporins (Nups), which together form around 1,000 protein subunits with a total molecular mass of about 110 MDa. The overall structure forms an octagonal complex with an outer diameter of roughly 100-120 nm and a central channel approximately 40-50 nm in diameter, embedded within the perinuclear space.^[36] The NPC architecture consists of a symmetric core scaffold flanked by asymmetric extensions. The core includes cytoplasmic and nuclear rings connected by a central framework, with the cytoplasmic ring anchoring short filaments and the nuclear ring supporting a basket-like structure. Key scaffold nucleoporins, such as Nup153, line the nuclear basket and contribute to anchoring the complex to the inner nuclear membrane, while the central channel is lined by FG-nucleoporins (FG-Nups) rich in phenylalanine-glycine repeats that form a hydrogel-like barrier. The Y-shaped Nup107-160 subcomplex forms the outer rings, providing structural stability and facilitating assembly.^[37]^[36] NPCs assemble through two primary mechanisms depending on the cell cycle stage. In post-mitotic cells, particularly in metazoans, NPCs are inserted into the reforming nuclear envelope during telophase, where pre-existing subcomplexes, such as the Nup107-160 scaffold, integrate into the double membrane. During interphase, de novo assembly occurs through the fusion of inner and outer nuclear membranes around a proto-pore structure formed by transmembrane Nups like Pom121 and Ndc1, allowing new NPCs to form without envelope breakdown.^[38]^[39] Regarding permeability, the NPC central channel permits passive diffusion of small molecules and ions up to approximately 40 kDa without energy input, while larger cargoes require active transport mediated by nuclear transport receptors. This size selectivity arises from the FG-Nups, which create a selective permeability barrier that restricts uncoated macromolecules above the diffusion limit through entropic exclusion and hydrophobic interactions.^[40]^[36]

Functions

Selective barrier and molecular transport

The nuclear envelope functions as a selective barrier that separates the nucleoplasm from the cytoplasm, preventing the free diffusion of most macromolecules while allowing controlled exchange through specialized channels. This barrier is primarily impermeable to molecules larger than approximately 40 kDa, such as proteins and RNAs, ensuring compartmentalization of cellular processes.^[36] Small molecules and ions below this size threshold, including metabolites and ions, can passively diffuse across the envelope via the nuclear pore complexes, which act as aqueous channels embedded in the double membrane.^[41]^[42] For macromolecules exceeding 40 kDa, transport across the nuclear envelope requires active mechanisms mediated by the nuclear pore complexes. This process is driven by a Ran-GTP gradient, where high concentrations of Ran-GTP in the nucleus promote cargo binding to exportins for outbound transport and release from importins for inbound delivery, while low cytoplasmic Ran-GTP levels facilitate the reverse.^[43]^[44] The energy for this directionality derives from GTP hydrolysis by Ran, catalyzed by RanGAP in the cytoplasm and maintained by the chromatin-bound nucleotide exchange factor RCC1 in the nucleus.^[43] Importins (karyopherin-β family members) recognize nuclear localization signals on cargo for import, while exportins bind nuclear export signals for export, enabling bidirectional shuttling of proteins, mRNAs, and ribonucleoprotein complexes.^[44] Central to this selectivity are the FG-nucleoporins, which line the nuclear pore complexes and feature phenylalanine-glycine (FG) repeats that form a hydrogel-like sieve or selective phase barrier. These intrinsically disordered FG domains interact via hydrophobic and multivalent bonds to create a mesh that excludes non-specific macromolecules but permits rapid transit of transport factor-cargo complexes, as importins and exportins transiently bind FG repeats to dissolve and re-form the barrier.^[45]^[46] This sieve mechanism ensures high fidelity, allowing only appropriately signaled cargoes to pass while maintaining the overall impermeability of the envelope.^[45] Nuclear pore complexes facilitate remarkably efficient transport, with each pore capable of mediating up to 1,000 translocations per second under physiological conditions, supporting the high flux required for cellular homeostasis.^[47]^[48] This rate underscores the pore's role as a dynamic gateway, balancing selectivity with speed through the coordinated action of the Ran cycle and FG sieve.^[47]

Role in chromatin organization and gene regulation

The nuclear envelope plays a pivotal role in organizing chromatin architecture by tethering specific genomic regions to its inner membrane and underlying lamina, thereby influencing gene expression patterns throughout the cell cycle. Inner nuclear membrane proteins, such as lamin B receptor (LBR) and LAP2β, along with nuclear lamina components, anchor chromatin loops to the nuclear periphery, forming stable associations that help compartmentalize the genome into active and repressive domains.^[49] This peripheral positioning is mediated by interactions between chromatin-binding proteins and lamina-associated domains (LADs), which constitute approximately 40% of the mammalian genome and are enriched in late-replicating, gene-poor regions.^[50] LADs represent key sites of chromatin tethering where heterochromatin is preferentially localized, promoting transcriptional repression through sequestration away from central nuclear transcription factories. Genes within or near LADs exhibit reduced expression due to this peripheral attachment, as demonstrated by genome-wide mapping techniques like DamID, which identified over 1,000 LADs in human fibroblasts associated with silencing histone marks such as H3K9me2/3 and H3K27me3.^[51] For instance, disruption of lamin B tethering leads to LAD detachment and derepression of silenced genes, underscoring the envelope's role in maintaining epigenetic boundaries.^[49] Additionally, nuclear envelope contacts facilitate interactions with transcription factors and epigenetic regulators; proteins like Lmo7 and Smads bind to inner membrane components, potentially sequestering activators or recruiting repressors like HDAC3 to deacetylate histones and silence nearby loci.^[50] Evidence from chromatin conformation capture studies, including Hi-C, reveals how nuclear envelope tethering shapes long-range chromatin interactions and impacts gene regulation. Hi-C data show that LADs form compact, self-interacting domains at the periphery with reduced contacts to transcriptionally active euchromatin, correlating with lower expression levels for peripheral genes.^[52] In lamin-depleted cells, Hi-C profiles indicate disrupted compartmentalization, with increased inter-LAD interactions and aberrant activation of repressed genes, highlighting the envelope's influence on 3D genome folding and regulatory fidelity. These spatial constraints also affect enhancer-promoter looping, where peripheral enhancers are often silenced, as seen in developmental contexts like adipogenesis where one-third of enhancers relocate to the envelope for repression.^[53]

Dynamics during cell division

Envelope breakdown

The nuclear envelope breakdown (NEBD) is a critical process during the early stages of mitosis in organisms undergoing open mitosis, allowing the spindle apparatus to access chromosomes. In animal cells, NEBD typically initiates during prophase and completes by prometaphase, coinciding with chromosome condensation and centrosome separation.^[54]^[55] The primary mechanism driving NEBD involves phosphorylation events orchestrated by cyclin-dependent kinase 1 (CDK1) in complex with cyclin B. CDK1 phosphorylates lamins, the intermediate filament proteins forming the nuclear lamina, at specific serine residues, which disrupts head-to-tail interactions and leads to lamina depolymerization.^[55] This depolymerization destabilizes the nuclear envelope's structural integrity, enabling membrane disassembly. Additionally, CDK1, along with polo-like kinase 1 (PLK1), phosphorylates inner nuclear membrane proteins and nucleoporins, such as Nup98 and Nup53, facilitating the initial disassembly of nuclear pore complexes (NPCs).^[54] Mechanical forces from early spindle microtubules contribute by inducing folds and tears in the lamina, with holes forming at sites of maximum tension, accelerating the breakdown process.^[56] Following lamina depolymerization, the inner and outer nuclear membranes fragment into small vesicles that disperse and integrate into the endoplasmic reticulum network.^[54] NPC disassembly proceeds in a stepwise manner, with peripheral nucleoporins releasing first, followed by the central scaffold, ensuring the envelope's complete dissolution.^[55] NEBD mechanisms vary across species, reflecting differences in mitotic strategies. In metazoans, such as mammals, open mitosis involves full envelope disassembly to permit spindle-chromosome interactions.^[54] In contrast, yeasts exhibit partial or closed mitosis; for instance, Schizosaccharomyces pombe maintains envelope integrity throughout, while Schizosaccharomyces japonicus undergoes limited breakdown during anaphase.^[54]

Envelope reformation

Nuclear envelope reformation occurs during telophase, following chromosome segregation in anaphase, as decondensing chromatin in daughter cells recruits nuclear components to re-establish the nucleocytoplasmic barrier.^[54] This process ensures the spatial separation of nuclear and cytoplasmic contents, completing the mitotic cycle.^[57] A key initial step involves the dephosphorylation of nuclear lamins, which were phosphorylated by mitotic kinases such as CDK1 during envelope breakdown to disassemble the nuclear lamina. Protein phosphatase 1 (PP1) primarily mediates this dephosphorylation in telophase, enabling lamins to polymerize and reform the supportive nuclear lamina beneath the inner nuclear membrane. Simultaneously, ER-derived membranes, which disperse the nuclear envelope components during mitosis, begin to envelop the chromatin surface, often forming sheet-like cisternae rather than discrete vesicles in metazoans.^[54] Fusion of these ER membranes is facilitated by SNARE proteins and GTPases like atlastins, creating a continuous double-membrane envelope around each set of chromosomes.^[58] The Ran-GTP gradient, generated by chromatin-bound RCC1, promotes this membrane recruitment and fusion by releasing importin-bound factors that otherwise inhibit assembly.^[59] Nuclear pore complex (NPC) reinsertion follows membrane enclosure, with nucleoporins reassembling in a chromatin-guided manner to restore selective transport. The nucleoporin ELYS (also known as MEL28) binds directly to decondensing chromatin via its AT-hook domains and recruits the Nup107-160 subcomplex, serving as a scaffold for sequential assembly of other nucleoporins into functional pores. This post-mitotic NPC biogenesis ensures hundreds to thousands of pores are positioned at chromatin surfaces, typically completing by early G1.^[60] Regulation of envelope sealing involves the ESCRT-III machinery, which resolves membrane gaps and annuli left by incomplete fusion or pore insertion during telophase. ESCRT-III filaments, nucleated by CHMP7 at LEM domain proteins like LEM2 on the inner membrane, constrict and sever these defects in a VPS4-dependent manner, preventing leakage and maintaining barrier integrity.^[57] This mechanism is conserved across eukaryotes undergoing open mitosis and is essential for viable nuclear reformation.30790-4)

Evolution and origins

Evolutionary emergence in eukaryotes

The nuclear envelope, a defining feature of eukaryotic cells, is believed to have emerged during the early evolution of eukaryotes through processes involving membrane remodeling in the ancestral cell. One prominent theory posits an inside-out origin, where the envelope formed via invagination of the endoplasmic reticulum (ER) from a prokaryotic ancestor, creating a double-membrane barrier around the genome to facilitate compartmentalization and material exchange with an ectosymbiotic proto-mitochondrion.^[61] In this model, extracellular membrane protrusions fused to enclose cytoplasmic components, with the inner nuclear membrane deriving from the original plasma membrane and the outer from the ER, establishing the perinuclear space and enabling selective transport.^[61] An alternative framework integrates this with the endosymbiotic model of eukaryogenesis, where an archaeal host cell engulfed an alphaproteobacterium that evolved into the mitochondrion; the nuclear envelope subsequently arose from invaginations of the archaeal host's plasma membrane, driven by the need to spatially separate transcription and translation amid increasing genomic complexity introduced by the symbiont.^[62] This process likely occurred after mitochondrial acquisition, as the envelope's formation helped protect splicing machinery from bacterial ribosomes and supported the evolution of linear chromosomes with introns.^[62] Fossil evidence supports this timeline, with the earliest unambiguous eukaryotic microfossils, such as acritarchs, appearing around 1.8 billion years ago in the Paleoproterozoic era, marking the rise of complex cellular organization.^[63] In the last eukaryotic common ancestor (LECA), the nuclear envelope featured primitive nuclear pore complexes (NPCs) that mediated essential nucleocytoplasmic transport, reflecting an already sophisticated barrier system. Comparative genomics reveals that core nucleoporins, the protein components of NPCs, are highly conserved across eukaryotic lineages, tracing back to LECA and underscoring the envelope's ancient origin as a stable innovation.^[64] These conserved elements, including FG-nucleoporins for selective permeability, indicate that the envelope's basic architecture was established prior to eukaryotic diversification.^[64]

Comparative features across organisms

The nuclear envelope in eukaryotes universally consists of a double lipid bilayer separated by the perinuclear space, perforated by nuclear pore complexes (NPCs) for selective transport, but exhibits notable structural and functional variations adapted to diverse cellular needs across organismal groups. In animals (metazoans), the inner nuclear membrane is supported by a robust nuclear lamina composed primarily of type A and C lamins (intermediate filaments) alongside type B lamins, which provide mechanical stability, organize chromatin, and anchor nuclear pore complexes.^[65] In contrast, plants share the canonical double-membrane architecture but lack lamins A and C, relying instead on alternative scaffolds such as crowded nuclear-associated proteins (e.g., CRWNs) and LEM-domain proteins like PNET2 to form a functional nuclear lamina that maintains envelope integrity and supports chromatin tethering.^[66] These differences reflect adaptations to plant-specific stresses, such as mechanical forces from turgor pressure, without compromising the envelope's barrier function.^[65] Fungi, including model yeasts like Saccharomyces cerevisiae and Schizosaccharomyces pombe, feature a nuclear envelope that undergoes closed mitosis, where the membrane remains largely intact but experiences partial disassembly of NPCs to permit spindle access and chromosome segregation.^[67] Their NPCs are structurally conserved with metazoan counterparts but smaller in overall mass (approximately 52 MDa versus 110 MDa in vertebrates), with fewer copies of certain nucleoporins, resulting in a more compact assembly that suits the compact fungal genome and rapid cell cycles.^[68] This partial NPC remodeling during mitosis—unlike the complete envelope breakdown in many animals—highlights an evolutionary adaptation for efficient division in walled cells.^[67] Among protists, the nuclear envelope displays greater diversity, with alveolates (e.g., dinoflagellates and apicomplexans) showing unique organizational features such as persistent nucleoli in close contact with the envelope, facilitating specialized chromatin dynamics in their often large, non-nucleosomal genomes.^[69] These variations may involve subtle membrane adaptations, though the core double-membrane structure persists. Exceptions include kinetoplastids like trypanosomes, where nuclear transport is atypical due to divergent NPC composition—lacking certain canonical nucleoporins—and reliance on specialized RNA export pathways adapted to polycistronic transcription and trans-splicing, enabling efficient gene expression in parasitic lifestyles.^[70] Such modifications underscore the envelope's plasticity in unicellular eukaryotes facing environmental pressures.

Clinical and pathological aspects

Laminopathies and nuclear envelope defects

Laminopathies represent a diverse group of rare genetic disorders primarily resulting from mutations in the LMNA gene, which encodes the A-type lamins essential for nuclear envelope integrity.^[71] These mutations disrupt the nuclear lamina, a meshwork of intermediate filaments underlying the inner nuclear membrane, leading to structural instability and impaired cellular functions.^[72] Over 15 distinct disorders have been linked to LMNA mutations, as well as defects in associated proteins like emerin (encoded by EMD), highlighting the broad clinical spectrum of these conditions.^[73] Among the most studied laminopathies is Hutchinson-Gilford progeria syndrome (HGPS), caused by a specific point mutation (c.1824C>T) in LMNA that activates a cryptic splice site, producing a truncated protein called progerin.^[74] This leads to accelerated aging phenotypes, including loss of subcutaneous fat, skeletal abnormalities, and cardiovascular disease, typically resulting in death around age 14.5 years from myocardial infarction or stroke, with treatments extending survival to nearly 20 years.^[71]^[75] LMNA mutations also underlie various muscular dystrophies, such as Emery-Dreifuss muscular dystrophy (EDMD), characterized by early contractures, progressive muscle weakness, and cardiac conduction defects.^[72] Additionally, dilated cardiomyopathy with conduction system disease is a common LMNA-related condition, often presenting with arrhythmias and heart failure, affecting up to 30% of carriers in some families.^[76] The pathological mechanisms of laminopathies involve defective nuclear lamina assembly, which compromises nuclear mechanics and leads to abnormal nuclear shapes, including lobulations and blebbing.^[77] These structural defects increase nuclear envelope fragility, promoting transient ruptures that allow DNA exposure to the cytoplasm, thereby inducing DNA damage through reactive oxygen species and activation of DNA damage response pathways like ATM and p53.^[78] In affected cells, such as fibroblasts from HGPS patients, persistent progerin accumulation exacerbates lamina disorganization, chromatin tethering disruptions, and genomic instability, contributing to premature cellular senescence.^[79] Similar mechanisms underlie muscle and cardiac pathologies, where mechanical stress on weakened nuclei triggers apoptosis and tissue degeneration.^[74] Diagnosis of laminopathies often relies on identifying characteristic nuclear abnormalities via microscopy, such as blebbing and irregular contours in patient-derived cells stained for lamin proteins.^[77] Genetic testing confirms LMNA or EMD variants, with over 500 pathogenic LMNA mutations reported as of 2025.^[73]^[80] Recent advances include CRISPR-Cas9-based models post-2020, such as iPSC-derived cardiomyocytes from LMNA-mutant patients corrected via base editing, which recapitulate disease phenotypes like nuclear deformation and enable testing of therapeutic interventions.^[81] Zebrafish models with LMNA knock-ins have also demonstrated skeletal muscle defects, providing in vivo insights into early-onset laminopathies.^[82] Therapeutic options include lonafarnib (Zokinvy), approved by the FDA in 2020, which extends average lifespan by about 25%. Emerging approaches as of 2025 include RNA therapies and nicotinamide mononucleotide (NMN) supplementation in preclinical models.^[83]^[84]

Interactions with pathogens and other disorders

The nuclear envelope (NE) serves as a critical barrier that pathogens, particularly viruses, must navigate to access the host nucleus for replication. Many viruses exploit the nuclear pore complexes (NPCs) embedded in the NE for genome delivery. For instance, herpesviruses dock their capsids at the NPC, where proteins like VP1/2 and UL25 facilitate a conformational change that ejects viral DNA through the pore, interacting with nucleoporins such as Nup214 and importin-β.^[85] Similarly, lentiviruses like HIV-1 form a pre-integration complex (PIC) containing viral DNA and capsid proteins, which translocates through the NPC in non-dividing cells via interactions with Nup153, Nup214, and transportin 3.^[85] Adenoviruses also dock at the NPC, partially disassembling with kinesin-1 assistance to release DNA, often involving protein VII and localized NPC disruption.^[85] Some viruses bypass or disrupt the NE entirely to gain nuclear access. Parvoviruses, for example, activate host caspases to induce NE breakdown, allowing viral entry without relying on NPCs, a mechanism that has been used to study mitotic triggers.^[86] Bacteria, while not entering the nucleus themselves, deploy effector proteins that traffic through NPCs to modulate host nuclear functions. Nucleomodulins from pathogens like Salmonella and Legionella contain nuclear localization signals (NLS) that enable import via the NPC, where they interfere with transcription, DNA repair, or immune signaling to promote infection.^[87] These interactions highlight the NE's role as a battleground in host-pathogen conflicts, often leading to altered nucleocytoplasmic transport and enhanced pathogen survival.^[88] Beyond infections, NE dysfunction contributes to various disorders, including cancer and neurodegenerative diseases. In cancer, alterations such as increased NPC density and NE rupture drive tumor progression by promoting genomic instability and metastasis. For example, loss of tumor suppressors like p53 or Rb enhances NE rupture frequency, allowing cytoplasmic DNA exposure and chromosomal aberrations that fuel carcinogenesis.^[89] NE proteins also influence mechanotransduction, where stiff tumor microenvironments weaken the envelope, facilitating invasion in cancers like breast and prostate.^[90] In neurodegenerative disorders, NE and NPC impairments disrupt nucleocytoplasmic transport, exacerbating protein aggregation and neuronal loss. In amyotrophic lateral sclerosis (ALS), C9orf72 mutations lead to nucleoporin depletion and TDP-43 mislocalization, clogging NPCs and impairing mRNA export.^[91] Alzheimer's disease involves tau and amyloid-β accumulation that damages NPCs, such as Nup62 and Nup98, causing nuclear invaginations and transport deficits in hippocampal neurons.^[91] Similar mechanisms occur in Huntington's and Parkinson's diseases, where mutant proteins sequester nucleoporins, underscoring the NE's vulnerability in age-related pathologies.^[91]

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Cytoskeletal Interactions at the Nuclear Envelope Mediated by ...
Nesprin-3 recruits intermediate filaments to the nuclear envelope in COS7 cells. COS7 cells stained for vimentin reveal the typical cytoskeletal staining ...
[19]
Nesprin-3, a novel outer nuclear membrane protein, associates with ...
The three cytoskeletal filament systems of eukaryotic cells are composed of actin filaments, intermediate filaments (IFs), and microtubules (MTs).
[20]
Mechanics of nuclear membranes | Journal of Cell Science
Jul 15, 2019 · The two membranes are separated by a fairly regular distance of ∼30 to 50 nm (Franke et al., 1981). These membranes are fused at hundreds of ...
[21]
The tethering of chromatin to the nuclear envelope supports ... - Nature
Jun 15, 2015 · Using optical tweezers, we find that isolated nuclei lacking inner nuclear membrane tethers are less stiff than wild-type nuclei and exhibit ...Missing: thickness | Show results with:thickness
[22]
Exploring the LINC to nuclear envelope spacing - PMC - NIH
LINC complexes are also thought to maintain a uniform gap of ∼50 nm between the outer and inner nuclear membranes. This perinuclear space widens in HeLa cells ...
[23]
Nuclear envelope: Current Biology - Cell Press
Mar 6, 2007 · The envelope is made up of inner and outer nuclear membranes, which enclose a lumen, the perinuclear space, which is continuous with the ...
[24]
Fluorescence Fluctuation Spectroscopy in the Perinuclear Space
The perinuclear space (PS) located within the nuclear envelope contains proteins involved in many cellular functions including cellular signaling, force ...
[25]
Nuclear Lamins - PMC - PubMed Central - NIH
The nuclear lamins are type V intermediate filament proteins that are critically important for the structural properties of the nucleus.
[26]
Nuclear lamins: Structure and function in mechanobiology - PMC
Feb 1, 2022 · The lamin family in mammals is subdivided into A-types [lamins A (LA) and C (LC)] and B-types [lamins B1 (LB1) and B2 (LB2)]. The LB1 and LB2 ...
[27]
Structural organization of nuclear lamins A, C, B1, and B2 revealed ...
The structural roles of lamins include maintenance of nuclear shape, nuclear positioning, and genome organization. In spite of the important role that lamins ...Lamin Isoforms Are Organized... · The Lamins Form Similar... · Figure 4
[28]
Nuclear lamina strain states revealed by intermolecular force ...
Jun 30, 2023 · ... inner nuclear membrane. The lamina is ~15-nm-thick protein meshwork, formed mainly from flexible ~400-nm-long A-type and B-type lamin ...
[29]
Nuclear lamins: key regulators of nuclear structure and activities - PMC
Lamins determine the shape and stiffness of the nucleus. Two of the main components that determine the shape and provide the strength to the nucleus are the ...
[30]
Nuclear lamins: major factors in the structural organization and ...
This review provides an up-to-date overview of the functions of nuclear lamins, emphasizing their roles in epigenetics, chromatin organization, DNA replication ...
[31]
Nuclear lamin phosphorylation: an emerging role in gene regulation ...
Phosphorylation of nuclear-peripheral lamins provides the mechanistic basis for nuclear lamina disassembly during the mitosis phase of the cell cycle. Nuclear ...
[32]
The Structure of the Nuclear Pore Complex (An Update) - PMC
In humans, each NPC consists of ~1,000 protein subunits, termed nucleoporins, and totals to a molecular mass of ~110 MDa—making the NPC one of the ...Missing: seminal papers
[33]
https://pmc.ncbi.nlm.nih.gov/articles/PMC4496104/
[34]
Mechanisms of nuclear pore complex assembly – two different ways ...
During nuclear growth after telophase, the NPCs assemble de novo into the double membrane barrier of the NE. Postmitotic NE and NPC assembly. Regulation of ...
[35]
A quantitative map of nuclear pore assembly reveals two ... - Nature
Jan 4, 2023 · During postmitotic assembly, the Y-complex is rapidly combined with components of the central ring, building the inner core of the pore within ...
[36]
Distinct, but not completely separate spatial transport routes in the ...
These FG Nups form a selective permeability barrier in the NPC that allows two modes of transport to occur: the passive diffusion of small molecules (< 40 kDa) ...
[37]
The selective permeability barrier in the nuclear pore complex - PMC
The barrier not only permits the passage of ions and other small molecules (< 40 kDa) via passive diffusion, but also simultaneously blocks the passage of ...Missing: impermeable | Show results with:impermeable
[38]
The permeability barrier of nuclear pore complexes appears to ...
Passive diffusion is fast for metabolites and small macromolecules, but becomes increasingly inefficient as the substrate approaches a size limit of 20–40 kDa ( ...
[39]
The molecular mechanism for nuclear transport and its application
There are four important factors for the nuclear transport: (1) nucleoporins (NUPs) that are constituent proteins of NPCs, (2) RanGTPase that allows for active ...
[40]
Nuclear transport proteins: structure, function and disease relevance
Nov 10, 2023 · In this review, we will explore the structure, function, and disease relevance of individual NTPs, with a focus on their interaction mechanism and networks.
[41]
'Natively unfolded' nucleoporins in nucleocytoplasmic transport
A high nuclear-RanGTP concentration promotes cargos binding to exportins and the dislocation of substrates from importins, while cytoplasmic conditions with low ...Missing: GTP | Show results with:GTP
[42]
The Permeability of Reconstituted Nuclear Pores Provides Direct ...
Aug 17, 2012 · We previously proposed a “selective phase model” in which the FG repeats interact with one another to form a sieve-like barrier that can be ...Results · Nup98 Is Essential For... · Experimental Procedures
[43]
Diameter dependence of transport through nuclear pore complex ...
Feb 20, 2024 · Remarkably, the NPC poses this selective barrier while enabling very high transport rates of ∼1000 molecules per second that traverse the pore, ...
[44]
Cargo transport through the nuclear pore complex at a glance
Jan 25, 2021 · Recent work has suggested that passive transport through the NPC might not have a strict size cut-off but rather act as a 'soft' permeability ...
[45]
https://pmc.ncbi.nlm.nih.gov/articles/PMC3104804/
[46]
The nuclear envelope as a chromatin organizer - PMC
The nuclear envelope (NE) is a double-membrane system with ... Investigation of the structure of the nuclear membrane by means of the electron microscope.
[47]
https://elifesciences.org/articles/87174
[48]
https://journals.biologists.com/jcs/article/134/2/jcs247874/237315/Cargo-transport-through-the-nuclear-pore-complex
[49]
https://doi.org/10.1016/j.molcel.2010.03.016
[50]
https://pmc.ncbi.nlm.nih.gov/articles/PMC3322583/
[51]
The Role of Phosphatases in Nuclear Envelope Disassembly ... - MDPI
Jul 7, 2019 · Nuclear Envelope Breakdown (NEBD) is a stage generally associated with the end of prophase and is directed by the phosphorylations of ...2. Nuclear Envelope... · 3. Nuclear Envelope... · 4. Nuclear Envelope...
[52]
https://doi.org/10.1038/nature06727
[53]
ESCRT-III controls nuclear envelope reformation - Nature
Jun 3, 2015 · ESCRT-III controls nuclear envelope reformation. Download PDF. Letter; Published: 03 June 2015. ESCRT-III controls nuclear envelope reformation.
[54]
Formation of the postmitotic nuclear envelope from extended ER ...
Aug 8, 2011 · It has been proposed that the postmitotic nuclear envelope arises by the fusion of mitotic ER tubules as they attach to the surface of the ...Missing: Strasburger | Show results with:Strasburger
[55]
GTP Hydrolysis by Ran Is Required for Nuclear Envelope Assembly
Generation of RanGTP by RCC1 and GTP hydrolysis by Ran are both required for the extensive membrane fusion events that lead to NE formation.
[56]
ELYS is a dual nucleoporin/kinetochore protein required for nuclear ...
Nuclear reassembly, which begins in late anaphase and continues through telophase, occurs at the chromatin periphery. ... To analyze the timing of ELYS ...
[57]
An inside-out origin for the eukaryotic cell | BMC Biology | Full Text
Oct 28, 2014 · We propose that eukaryotes evolved from a prokaryotic cell with a single bounding membrane that extended extracellular protrusions that fused to give rise to ...
[58]
Endosymbiotic theories for eukaryote origin - PMC - PubMed Central
We have compiled a survey of endosymbiotic theories for the origin of eukaryotes and mitochondria, and for the origin of the eukaryotic nucleus.
[59]
Fossil Record of the Eukaryota
More probable eukaryote fossils begin to appear at about 1.8 billion years ago. These are spherical fossils of likely algal protists, called acritarchs.Missing: envelope 1.8-2
[60]
Comparative Genomic Evidence for a Complete Nuclear Pore ...
Our results indicate that all major protein subcomplexes in the Nuclear Pore Complex are traceable to the Last Eukaryotic Common Ancestor (LECA). In ...
[61]
“Laminopathies:” a wide spectrum of human diseases - PMC
Mutations in genes encoding the intermediate filament nuclear lamins and associated proteins cause a wide spectrum of diseases sometimes called “laminopathies.”
[62]
Laminopathies; Mutations on single gene and various human ... - NIH
Mutations on Lamin A or related genes induce a very diverse spectrum of human diseases ranging from muscular dystrophy to progeria.
[63]
The structural and gene expression hypotheses in laminopathic ...
Jul 15, 2019 · Today, more than 400 different LMNA mutations are known (www.umd.be/LMNA/), which give rise to more than 15 different diseases, affecting a wide ...
[64]
Genetic and Pathophysiological Basis of Cardiac and Skeletal ...
Aug 20, 2024 · Mutations in lamins result in laminopathies, a group of diseases including muscular dystrophies, Hutchison–Gilford progeria syndrome, and cardiomyopathies with ...
[65]
The Broad Spectrum of LMNA Cardiac Diseases: From Molecular ...
Jul 3, 2020 · Mutations in the LMNA gene cause laminopathies, a group of disorders characterized by phenotypically heterogeneous manifestations. Up to now a ...Lmna Gene And Its Products · From Lmna Variants To... · Mouse Models
[66]
DNA Damage and Lamins - PMC - PubMed Central - NIH
New evidence indicates that A-type lamins play a key role maintaining telomere localization, structure, length and function, keeping in check the levels of ROS.
[67]
Nuclear proteostasis imbalance in laminopathy‐associated ...
Jul 25, 2023 · Deregulation of nuclear proteostasis by mutant LMNA leads to loss of nuclear protein quality control, DNA damage, altered chromatin dynamics, ...
[68]
LMNA Co-Regulated Gene Expression as a Suitable Readout after ...
Dec 8, 2022 · LMNA missense mutations are becoming correctable with CRISPR/Cas9-derived tools. Evaluating the functional recovery of LMNA after gene editing ...
[69]
A CRISPR/Cas9 zebrafish lamin A/C mutant model of muscular ...
Oct 2, 2021 · This study presents an animal model of skeletal muscle laminopathy where heterozygous and homozygous lmna mutants exhibit prominent skeletal muscle ...
[70]
Virus strategies for passing the nuclear envelope barrier - PMC
Research in recent years indicates that the nuclear envelope is a major hurdle for many viruses.Virus Strategies To Overcome... · Herpesviruses · Lentiviruses
[71]
Parvoviruses Cause Nuclear Envelope Breakdown by Activating ...
Here we used the ability of parvoviruses to induce nuclear membrane breakdown to understand the triggers of key mitotic enzymes.
[72]
Bacterial nucleomodulins: A coevolutionary adaptation to the ...
Jan 21, 2021 · Bacterial nucleomodulins are an emerging family of pathogen effector proteins that evolved to target specific components of the host cell command center ...<|control11|><|separator|>
[73]
Nuclear warfare: pathogen manipulation of the nuclear pore ...
Mar 20, 2025 · Viruses and bacteria exploit the nuclear pore complex (NPC) and host nuclear functions to bypass cellular barriers and manipulate essential processes.
[74]
Nuclear Envelope Rupture Is Enhanced by Loss of p53 or Rb
Thus, NE rupture may change the genomic landscape in cancer cells, thereby contributing to carcinogenesis. Because we show that p53- or Rb-deficient cells can ...
[75]
Nuclear envelope proteins, mechanotransduction, and their ... - Nature
May 5, 2025 · Lamins A/C are major components of the nuclear lamina and regulate nuclear mechanics and stability, but also interact with chromatin and ...<|control11|><|separator|>
[76]
The nuclear envelope and nuclear pore complexes in ... - Frontiers
Recent research has highlighted a strong link between dysfunction of the NE and NPCs and the onset of neurodegenerative disorders.