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Nuclear pore complex

The nuclear pore complex (NPC) is a massive protein assembly (~110 MDa) embedded within the double lipid bilayer of the nuclear envelope in eukaryotic cells, serving as the essential and sole bidirectional gateway for the selective exchange of macromolecules—such as proteins, RNAs, and ribonucleoprotein particles—between the nucleus and cytoplasm.^[1] Composed of approximately 30–35 distinct nucleoporins (Nups) arranged in multiple copies to form ~500–1,000 protein subunits overall, the NPC exhibits eightfold rotational symmetry and spans the nuclear envelope with a central transport channel of ~40–50 nm in diameter, enabling the passage of cargoes up to ~39 nm while restricting unauthorized entry.^[2] This structure maintains nuclear integrity by establishing a selective permeability barrier primarily through phenylalanine-glycine (FG)-repeat domains on certain Nups, which form a dynamic, hydrogel-like mesh that permits passive diffusion of small molecules (<40–60 kDa) but requires active, receptor-mediated transport for larger entities.^[3] The NPC's architecture consists of a conserved symmetric core scaffold, including concentric inner and outer rings formed by Y-shaped and β-propeller/α-helical nucleoporin subcomplexes (e.g., Nup107-160 and Nup93), which anchor to the nuclear membranes via transmembrane Nups like Pom121 and Ndc1.^[1] Asymmetric extensions, such as flexible cytoplasmic filaments (e.g., Nup358/RanBP2) and a nuclear basket (anchored by Nup153 and Tpr), further modulate transport directionality and cargo processing.^[2] Recent near-atomic resolution structures, achieved through integrative approaches like cryo-electron tomography, subtomogram averaging, and AlphaFold modeling, have unveiled the NPC's inherent flexibility, including channel dilation under mechanical stress (up to ~60 nm) and species-specific variations, such as a more compact ~52 MDa yeast NPC compared to the human version.^[1] These insights underscore the NPC's evolutionary conservation across eukaryotes while highlighting adaptations in metazoans for enhanced complexity in mRNA export and nuclear import.^[3] Functionally, the NPC orchestrates nucleocytoplasmic transport via the Ran GTPase cycle, where importins (karyopherins) escort nuclear localization signal-bearing cargoes inward and exportins handle nuclear export signals outward, with FG-repeats serving as docking sites for these receptors to traverse the barrier efficiently.^[4] Beyond transport, NPCs influence gene expression by tethering chromatin and transcription factors, contribute to DNA repair at nuclear peripheries, and act as mechanosensors, relaying cytoskeletal forces to regulate pathways like YAP signaling.^[1] Disruptions in NPC components, such as mutations in ~24 Nups, are implicated in diseases including acute leukemias, congenital heart defects, and neurodegenerative conditions, while viruses like HIV exploit the NPC for nuclear entry, underscoring its therapeutic relevance.^[2]

Overview

Definition and location

The nuclear pore complex (NPC) is a massive protein assembly, weighing approximately 110 MDa in vertebrates and comprising around 1,000 protein subunits, that perforates the nuclear envelope to create selective aqueous channels for the exchange of macromolecules between the nucleus and cytoplasm.^[2] This structure serves as the primary gateway for nucleocytoplasmic transport, enabling the regulated movement of essential cellular components such as proteins, RNAs, and ribonucleoprotein complexes while maintaining the integrity of the nuclear compartment.^[5] NPCs are embedded directly within the double lipid bilayer of the nuclear envelope, which encapsulates the nucleus and is contiguous with the endoplasmic reticulum membrane system.^[2] In mammalian cells, nuclei typically contain 3,000–5,000 NPCs, which are evenly distributed across the envelope's surface with an average center-to-center spacing of approximately 100–150 nm.^[6]^[7] This dense arrangement ensures efficient coverage, occupying a significant portion of the nuclear surface to support high-volume traffic demands.^[8] At its core, the NPC functions as a bidirectional conduit that permits passive diffusion of small molecules and ions below ~40 kDa while imposing a selective barrier on larger macromolecules, which require energy-dependent active transport mechanisms to traverse.^[2] This size-selective permeability is crucial for cellular homeostasis, allowing rapid equilibration of small solutes without compromising the compartmentalization of genetic material and regulatory factors.^[9] The NPC represents a defining feature of eukaryotic cellular organization, being universally present across all eukaryotic lineages from yeast to humans, yet entirely absent in prokaryotes, which lack a membrane-bound nucleus.^[10] Its evolutionary conservation underscores its indispensable role in the development of nuclear compartmentalization during the transition to complex eukaryotic life.^[5]

Historical discovery

The nuclear pore complex (NPC) was first observed in the mid-20th century through pioneering electron microscopy studies of the nuclear envelope. In 1954, M.L. Watson provided one of the earliest descriptions of pores in the mammalian nuclear membrane, identifying circular openings approximately 50 nm in diameter within the double-layered envelope of rat liver cells.^[11] These structures were initially viewed as simple perforations, but subsequent work in the 1950s, such as the 1950 study by H.G. Callan and S.G. Tomlin on the fine structure of the nuclear membrane in amphibian oocytes using electron microscopy, helped establish the pores as integral features of eukaryotic nuclei.^[12] George E. Palade advanced electron microscopy techniques to visualize cellular organelles, laying foundational insights into cellular architecture, though his primary focus was on broader compartments like the endoplasmic reticulum. Don W. Fawcett played a key role in popularizing the term "nuclear pores" during the 1960s through his detailed histological and ultrastructural analyses, emphasizing their role as potential channels for nuclear-cytoplasmic exchange in diverse cell types. By the 1970s, the functional significance of these pores began to emerge, particularly through microinjection experiments that confirmed their involvement in macromolecular transport. Carl M. Feldherr and colleagues demonstrated in the early 1990s that colloidal gold particles up to 26 nm in diameter could traverse the nuclear envelope via pores, providing direct evidence that NPCs serve as conduits for selective material passage rather than passive diffusion sites.^[13] This shifted perceptions from static structural elements to dynamic gateways. In the 1980s, structural biologists like Werner W. Franke advanced characterization by identifying subcomponents of the NPC, such as annuli and spokes, using high-resolution electron microscopy on amphibian oocyte envelopes, which revealed the pore's octagonal symmetry and proteinaceous nature.^[14] Early hints of regulatory mechanisms appeared, with studies suggesting energy-dependent processes involving GTP hydrolysis for transport directionality. The late 1980s and 1990s marked a transition to molecular insights, as the first nucleoporins (Nups) were cloned; for instance, J. Sukegawa and G. Blobel isolated rat Nup153 in 1993, a zinc finger-containing protein localized to the nuclear basket, highlighting the NPC's protein complexity and FG-repeat motifs essential for selectivity.^[15] These developments underscored the NPC's evolution from a mere "pore" to a sophisticated, dynamic multiprotein assembly.

Molecular composition

Nucleoporins (Nups)

Nucleoporins (Nups) are the protein building blocks of the nuclear pore complex (NPC), with approximately 30 distinct types identified in yeast and around 30–34 in vertebrates, though the latter assemble into larger complexes with up to 1,000 subunits per NPC.^[16] These proteins are broadly classified into scaffold Nups, which provide the structural framework; FG-Nups, containing phenylalanine-glycine (FG) repeats that establish the selective permeability barrier; transmembrane Nups, which anchor the NPC to the nuclear envelope; and peripheral Nups, which form extensions such as cytoplasmic filaments and the nuclear basket.^[17] This classification reflects their roles in maintaining NPC integrity and facilitating nucleocytoplasmic exchange. Key scaffold Nups include the Nup107-160 subcomplex (also known as the Y-complex), which forms a stable outer ring and is essential for NPC architecture, as well as Nup93 and Nup188, which contribute to the inner ring.^[16] Prominent FG-Nups are Nup98, located in the central channel and filaments, and Nup153, part of the nuclear basket, both featuring disordered FG-repeat domains that interact with transport receptors.^[17] Transmembrane Nups such as Pom121 and Ndc1 embed in the pore membrane, linking the scaffold to the nuclear envelope and ensuring positional stability.^[16] The FG-repeats in about one-third of Nups consist of intrinsically disordered, hydrophobic sequences (e.g., FxFG, GLFG motifs) that coalesce into a hydrogel-like or phase-separated meshwork, creating a sieve that permits diffusion of small molecules while selectively allowing nuclear transport receptors to traverse with cargoes.^[18] Post-translational modifications, including O-GlcNAcylation on multiple Nups to regulate stability and assembly, phosphorylation (e.g., on Nup98 during mitosis to modulate transport), and SUMOylation or ubiquitination on peripheral Nups like Nup153 to control dynamics, fine-tune NPC function in response to cellular signals.^[19]^[20]^[21] The core scaffold Nups exhibit high conservation across eukaryotes, traceable to the last eukaryotic common ancestor, enabling a universal NPC framework from yeast to humans, whereas vertebrate-specific expansions occur in FG- and peripheral Nups, increasing complexity and regulatory potential.^[22]^[23]

Stoichiometry and symmetry

The nuclear pore complex (NPC) in vertebrates consists of approximately 30–34 distinct nucleoporins (Nups), assembled into roughly 500–1,000 protein subunits per NPC, with copy numbers typically following multiples of 8 due to the structure's rotational symmetry.^[24] This stoichiometry contributes to a total molecular mass of about 110–125 MDa for the human or vertebrate NPC, significantly larger than the ~60–66 MDa observed in yeast, reflecting evolutionary expansions in peripheral elements and FG-nucleoporins.^[24]^[25] Quantitative mass spectrometry and super-resolution microscopy have confirmed these totals, revealing cell-type variations but a conserved core composition across metazoans.^[26] The NPC exhibits eightfold rotational symmetry in its central scaffold, organizing nucleoporins into concentric rings that span the nuclear envelope, while peripheral domains introduce asymmetry. For instance, the Nup107-160 subcomplex, a key scaffold component, occurs in 16 copies (8 per outer ring on the cytoplasmic and nuclear sides), forming the structural backbone.01416-5) In contrast, FG-nucleoporins like Nup98 are present in higher numbers, with approximately 32–48 copies per NPC, creating a dense, disordered barrier within the central channel.^[24] Asymmetric features include the nuclear basket, anchored by 8 copies of Nup153, and cytoplasmic filaments extending from 8 copies of Nup358, which facilitate directionality in transport without mirroring the opposite side's organization.^[27] Recent structural studies using cryo-electron microscopy (cryo-EM) and cryo-electron tomography have resolved nearly 90% of the vertebrate NPC's components at near-atomic resolution, enabling precise quantification of stoichiometries in the symmetric core and asymmetric peripherals. A 2022 cryo-EM analysis of the human NPC's cytoplasmic face, for example, docked major filament nucleoporins like the heterohexameric cytoplasmic filament nucleoporin complex (~540 kDa) and Nup358 pentamers onto symmetric ring scaffolds, confirming the eightfold arrangement while highlighting modular asymmetries.^[28] These advancements build on earlier integrative models, providing a near-complete atomic blueprint that underscores the NPC's stoichiometric precision as essential for its transport fidelity.01416-5)

Architecture

Overall organization

The nuclear pore complex (NPC) is a large macromolecular assembly embedded in the nuclear envelope, with an overall outer diameter of approximately 105–120 nm, an inner channel diameter of about 50–60 nm, and a height of roughly 65–80 nm that spans the inner and outer nuclear membranes.^[29]^[28] This architecture accommodates bidirectional transport while maintaining nuclear integrity.^[28] At its core, the NPC features a stable scaffold formed by inner and outer ring complexes, including the Y-shaped coat nucleoporin complex and the β-propeller/α-helical inner ring subcomplexes (e.g., Nup107-160 and Nup93), which exhibit eightfold rotational symmetry and are anchored to the nuclear membranes by transmembrane nucleoporins such as Pom121 and Ndc1.^[28]^[3] This configuration provides structural rigidity and serves as the foundation for peripheral attachments. The architecture exhibits species-specific variations, with the human NPC being larger and more complex than the yeast counterpart (~52 MDa).^[1] Peripheral structures extend from this core scaffold: a cup-like nuclear basket on the nucleoplasmic side, measuring approximately 100 nm in width, and eight flexible cytoplasmic filaments on the other side, each extending about 50 nm into the cytoplasm.^[3] The scaffold integrates with the nuclear lamina via interactions involving inner nuclear membrane proteins and connects to the cytoskeleton through linker complexes such as LINC (linker of nucleoskeleton and cytoskeleton), which transmit mechanical forces across the envelope.^[30] Recent cryo-electron microscopy studies, including a 2022 integrative model, have resolved the full scaffold at high resolution, confirming these organizational features.^[28]

Central channel and selectivity barrier

The central channel of the nuclear pore complex (NPC) forms a conduit approximately 50–60 nm in diameter (as measured in recent in situ studies), serving as the primary pathway for nucleocytoplasmic transport.^[29] This channel is lined by intrinsically disordered domains of phenylalanine-glycine (FG)-rich nucleoporins (FG-Nups), which extend into the lumen to create a sieve-like mesh with an effective pore size of about 5 nm. The arrangement of these FG-Nups, anchored to the NPC scaffold, generates a dense, dynamic barrier that fills much of the channel volume, estimated at 30–50 nm in effective width across species.^[31]^[32]^[33] The selectivity barrier arises primarily from the FG-repeats within these nucleoporins, which impose entropic exclusion on non-specific molecules through steric repulsion and electrostatic effects due to their low charge density and flexible, brush-like extensions. In the "selective phase" model, the hydrophobic FG motifs drive cohesive interactions, forming a hydrogel-like network that excludes inert macromolecules while permitting transient dissolution by nuclear transport receptors (NTRs) bound to cargo, thus enabling selective passage. This barrier maintains nuclear integrity by restricting free diffusion to small molecules below approximately 40–60 kDa, such as ions and metabolites, while larger entities require facilitated transport.^[34]^[35]^[32] For active transport, the barrier accommodates cargoes up to about 39 nm in diameter when complexed with NTRs, including large structures like ribosomal subunits (25–30 nm). Two prominent models describe this selectivity: the reduction-of-dimensionality model, where FG-Nups collapse into low-dimensional layers that guide NTR-cargo complexes along the channel walls via multivalent interactions, enhancing efficiency; and the virtual gating model, positing a fluctuating entropic brush of FG domains that creates a size- and affinity-dependent energy landscape, allowing selective permeation without a fixed physical sieve. These models highlight the barrier's adaptability, with experimental evidence from NPC mimics supporting both through observations of density gradients and transport kinetics.^[33]^[34]

Peripheral domains

The nuclear basket forms a meshwork-like structure on the nuclear side of the nuclear pore complex (NPC), extending from the inner nuclear ring and serving as a platform for cargo processing prior to export. Composed primarily of the nucleoporins Nup153, Nup50, and Tpr in mammals, the basket features eight struts formed by coiled-coil bundles of Tpr that converge into globular distal densities, as revealed by high-resolution cryo-electron microscopy (cryo-EM) structures. These struts are anchored to a double nuclear ring via a latch mechanism involving Nup153, providing structural stability and flexibility. The basket extends approximately 15–30 nm from the central plane of the NPC, creating a confined space for transient interactions.^[36] Functionally, the nuclear basket plays a key role in mRNA retention and export licensing by acting as a docking site for messenger ribonucleoprotein (mRNP) complexes at its distal densities. It facilitates cargo maturation through recognition of poly-A tail features on mRNAs, ensuring quality control and preventing premature export of immature transcripts. This retention mechanism provides additional time for nuclear processing events, such as splicing and polyadenylation, before licensed mRNPs are released into the central channel for transport.^[36] On the cytoplasmic side, the filaments project as flexible extensions from the NPC's outer ring, comprising Nup358 (also known as RanBP2) and Nup214 as major components. Nup358 forms pentameric bundles of α-helical solenoids and coiled-coil elements, projecting up to 60 nm into the cytoplasm and anchoring to the coat nucleoporin complex (CNC), while Nup214 integrates into a heterohexameric cytoplasmic filament nucleoporin complex (CFNC) with a central coiled-coil hub positioned above the transport channel. Cryo-EM and cryo-electron tomography have elucidated their asymmetric distribution, with Nup358 filaments extending outward for dynamic interactions and CFNC overseeing channel-proximal remodeling. These structures create docking sites for export complexes, including binding platforms for RanGAP1 via Nup358's Ran-interacting and E3 ligase domains. The cytoplasmic filaments contribute to cargo processing by promoting the disassembly of transport complexes post-translocation, ensuring efficient recycling of components like importins and exportins. Nup358, in conjunction with RanGAP1, catalyzes the hydrolysis of Ran-GTP in export complexes, facilitating their irreversible dissociation and release into the cytoplasm. This disassembly step is crucial for terminating transport cycles and preventing backlog at the NPC, with CFNC aiding in mRNP remodeling to prepare cargoes for cytoplasmic fate.

Nuclear transport

Protein import

The classical nuclear protein import pathway facilitates the translocation of proteins bearing a nuclear localization signal (NLS) into the nucleus through the nuclear pore complex (NPC). Proteins destined for the nucleus typically contain a classical NLS, which consists of one or more clusters of basic amino acids such as lysine and arginine; monopartite NLSs feature a single stretch of 4–8 basic residues, while bipartite NLSs have two such clusters separated by a 10–12 amino acid linker. These signals are recognized in the cytoplasm by the adaptor protein importin α, which binds the NLS via its armadillo repeat domain, forming a complex that is subsequently bridged to importin β (also known as karyopherin β1). The resulting ternary complex—cargo protein, importin α, and importin β—interacts with phenylalanine-glycine (FG) repeats on nucleoporins within the NPC central channel, enabling facilitated diffusion across the nuclear envelope.^[37]^[6] Directionality and energy for this import process are provided by the Ran GTPase cycle, which establishes a RanGTP gradient across the nuclear envelope: high concentrations of RanGTP in the nucleus and low in the cytoplasm. In the nucleus, chromatin-bound RCC1 (Ran guanine nucleotide exchange factor) converts RanGDP to RanGTP, promoting the binding of RanGTP to importin β and thereby dissociating the cargo-importin complex to release the protein. The importins are then recycled to the cytoplasm: importin β forms a complex with RanGTP for export, while importin α is exported via the exportin CAS in association with RanGTP. On the cytoplasmic side, RanGAP (Ran GTPase-activating protein) stimulates GTP hydrolysis on Ran, converting RanGTP to RanGDP and releasing the importins for reuse; this hydrolysis step ensures the unidirectionality of transport by preventing re-binding of cargo outside the nucleus.^[37]^[16]^[38] While the classical pathway handles the majority of NLS-bearing cargos, non-classical import mechanisms exist for certain proteins lacking a standard NLS, such as core histones, which rely on direct interactions with FG-nucleoporins or specialized importins like importin 7 or transportin. These pathways often involve piggybacking on other nuclear proteins or sequence-specific motifs like the PY-NLS, allowing passage through the NPC without importin α/β mediation. The NPC imposes size constraints, permitting passive diffusion for molecules under 40-60 kDa but requiring active transport for larger cargos; individual transits occur rapidly, with dwell times of approximately 5-10 ms, supporting a throughput of approximately 1000 cargos per second per pore under physiological conditions.^[6]^[39]^[40]

Protein export

Protein export through the nuclear pore complex (NPC) primarily involves proteins bearing a nuclear export signal (NES), a short hydrophobic sequence typically rich in leucine residues that directs them from the nucleus to the cytoplasm. The key export receptor, CRM1 (also known as exportin 1 or XPO1), recognizes and binds NES-containing cargo proteins in the nucleus only in the presence of RanGTP, forming a stable ternary complex consisting of the cargo, CRM1, and RanGTP.^[41] This cooperative binding is facilitated by conformational changes in CRM1 induced by RanGTP, which creates high-affinity NES-binding grooves on the receptor's surface.^[42] The resulting complex interacts sequentially with phenylalanine-glycine (FG) repeats on nucleoporins within the NPC central channel, enabling facilitated diffusion across the permeability barrier.^[43] Directionality of export is strictly controlled by the Ran GTPase cycle, which maintains a nuclear RanGTP gradient due to the localization of RCC1 (Ran guanine nucleotide exchange factor) in the nucleus and RanGAP (Ran GTPase-activating protein) in the cytoplasm. Upon translocation to the cytoplasmic side of the NPC, RanGAP, often in complex with RanBP1 (Ran-binding protein 1) and RanBP2 (a nucleoporin), accelerates GTP hydrolysis on Ran, converting RanGTP to RanGDP and triggering disassembly of the export complex.^[44] This irreversible step releases the NES-cargo in the cytoplasm, preventing re-import and ensuring unidirectional transport, while CRM1 and RanGDP recycle back to the nucleus.^[45] In contrast to protein import, which uses importins bound to RanGDP, the export process relies on RanGTP for cargo loading, highlighting the Ran's role in establishing vectorial transport across the NPC.^[46] Notable examples of CRM1-dependent export include transcription factors such as NFAT (nuclear factor of activated T cells) and STAT3 (signal transducer and activator of transcription 3), which shuttle to the cytoplasm to modulate signaling pathways like immune response and cell proliferation.^[47] Similarly, mRNA-binding proteins like HuR (human antigen R), which stabilizes AU-rich element-containing mRNAs, are exported via CRM1 to regulate post-transcriptional gene expression in the cytoplasm.^[48] CRM1 mediates the export of hundreds of such proteins, underscoring its role as a versatile receptor in cellular homeostasis.^[49] The kinetics of protein export mirror those of import, with dwell times in the NPC on the order of 5 milliseconds per transit event. Under physiological conditions, each NPC supports a throughput of approximately 1,000 protein molecules per second, enabling rapid adaptation to cellular demands without rate-limiting bottlenecks.^[50]

RNA export

The nuclear pore complex (NPC) facilitates the export of various RNA species from the nucleus to the cytoplasm, ensuring proper gene expression and cellular function. Unlike protein export, which primarily relies on nuclear export signals (NES) and exportins like CRM1, RNA export employs specialized adaptors and receptors that interact with the FG-nucleoporin barrier of the NPC. These pathways are RNA-type specific, with mRNA, rRNA, tRNA, snRNA, and miRNA each utilizing distinct mechanisms to traverse the NPC while maintaining directionality and fidelity.^[51] mRNA export represents the predominant RNA trafficking route through the NPC, involving the transcription-export (TREX) complex, which couples mRNA processing to nuclear export. The TREX complex, conserved from yeast to humans, assembles on nascent transcripts during splicing and includes subunits such as THO, Sub2/UAP56, and ALYREF (Yra1 in yeast), which bind the mRNA and recruit the export receptor NXF1/NXT1 heterodimer (Mex67/Mtr2 in yeast). ALYREF acts as a key adaptor, bridging the mRNP to NXF1/NXT1 via direct interactions, thereby licensing the mRNA for translocation through the NPC's central channel by binding FG-repeats on nucleoporins.^[52]^[53] Directionality is enforced by the DEAD-box helicase Dbp5 (DDX19 in humans), localized at the cytoplasmic fibrils of the NPC, which ATP-dependently remodels the mRNP upon Gle1- and IP6-mediated activation, dissociating NXF1/NXT1 and preventing re-import.^[51] This process occurs rapidly, with individual mRNPs translocating through the NPC in approximately 200 milliseconds.^[51] Ribosomal RNA (rRNA) export, essential for ribosome biogenesis, also utilizes the NPC and shares components with mRNA pathways. Pre-ribosomal subunits, including pre-40S and pre-60S particles containing rRNA, are exported via the Mex67/Mtr2 (NXF1/NXT1) receptor in yeast, which binds these cargoes through distinct surface patches involving loop insertions that interact electrostatically with 5S rRNA.^[54] In mammals, analogous mechanisms involve NXF1/NXT1, facilitating the passage of large pre-ribosomal complexes through the NPC without dedicated exportins.^[54] Transfer RNA (tRNA) export employs dedicated karyopherins for selectivity. Mature tRNAs are primarily exported by exportin-t (XPO-t, Los1 in yeast), a RanGTP-binding receptor that cooperatively recognizes the processed tRNA structure, particularly the TΨC and acceptor arms, ensuring only end-processed tRNAs are transported through the NPC.^[55] Under stress conditions or for specific subsets, CRM1 (XPO1) serves as an alternative exporter for certain tRNAs, often in conjunction with adaptors.^[56] Small nuclear RNA (snRNA) and microRNA (miRNA) follow minor, specialized pathways. snRNAs, critical for splicing, are exported as m7G-capped precursors via CRM1, which recognizes the RNA through the adaptor PHAX (phosphorylated adaptor for RNA export); PHAX binds the cap-binding complex (CBC) and facilitates RanGTP-dependent translocation via the NPC.^[57] Similarly, pre-miRNAs are exported by exportin-5 (XPO5), which specifically binds the characteristic hairpin structure of pre-miRNAs in a RanGTP-dependent manner, delivering them to the cytoplasm for Dicer processing into mature miRNAs.^[58] In mammalian cells, the NPC handles substantial bulk flow of RNA, exporting hundreds of thousands of mRNA transcripts per cell to support protein synthesis demands. The cytoplasmic basket of the NPC, anchored by nucleoporins like Nup358 and Tpr, plays a role in post-export surveillance, retaining aberrant mRNPs for degradation while allowing functional ones to dissociate into the cytoplasm.^[59]^[51]

Additional functions

Gene regulation

The nuclear pore complex (NPC) plays a pivotal role in transcriptional control through interactions between peripheral nucleoporins (Nups) and chromatin, facilitating the positioning of genes near the nuclear periphery. Specifically, Nup153, a key component of the nuclear basket, binds to chromatin via its zinc finger domains, anchoring active gene loci to NPCs in a process known as gene gating. This tethering enhances the efficiency of transcription by organizing chromatin in proximity to the NPC, where it can couple gene expression with downstream nuclear export pathways.^[60]^[61] In yeast, the NPC promotes inducible gene expression by relocating activated genes to the nuclear periphery upon stimulation. For instance, genes such as INO1 and GAL1 associate with NPCs through interactions involving Nups like Nup1 and Nup60, which serve as scaffolds to boost transcription rates and poise genes for rapid activation. This mechanism ensures robust expression of stress-responsive or nutrient-sensing genes, highlighting the NPC's role as a regulatory platform beyond mere transport.^[62]^[63] In mammals, NPCs link to super-enhancers, clusters of regulatory elements that drive high-level expression of cell identity genes. Nup153's intrinsically disordered regions trap super-enhancers at the nuclear periphery, as demonstrated in cancer cells where this association amplifies oncogenic transcription programs, such as those involving TP63.^[64] Recent studies from the 2020s further reveal the NPC functioning as a signaling hub for transcription factors, where peripheral Nups recruit and modulate factors like TPR to fine-tune gene expression in response to cellular cues.^[65] Additionally, the NPC contributes to DNA repair by anchoring repair factors at double-strand breaks (DSBs). Nup153 facilitates the nuclear import and localization of 53BP1, a key mediator in non-homologous end joining, to DSB sites near the nuclear envelope, promoting efficient repair and genome stability. This peripheral anchoring mechanism is conserved across eukaryotes and underscores the NPC's integration of repair processes with chromatin organization.^[66]^[67]

Interactions with pathogens

The nuclear pore complex (NPC) serves as a critical gateway that pathogens, particularly viruses and bacteria, exploit to facilitate their lifecycle by hijacking nuclear transport mechanisms or disrupting NPC architecture. Viruses such as HIV-1 and influenza A have evolved strategies to interact with specific nucleoporins (Nups) to enable the import or export of viral components, thereby bypassing the NPC's selectivity barrier. Similarly, bacterial effectors can mimic host nuclear localization signals (NLS) or nuclear export signals (NES) to translocate into the nucleus, modulating host gene expression for pathogen benefit. These interactions highlight the NPC's vulnerability during infection, though host cells counter with modifications like SUMOylation to limit pathogen access. HIV-1 exemplifies viral hijacking of the NPC during nuclear import of its pre-integration complex (PIC). The conical capsid of HIV-1 directly engages FG-repeat nucleoporins (FG-Nups), including Nup153 and Nup358 (also known as RanBP2), mimicking the binding mode of karyopherins to traverse the NPC without classical transport receptors. Nup153, located on the nuclear basket, unlocks the NPC for HIV-1 translocation in nondividing cells by interacting with the capsid's N-terminal domain, facilitating docking and passage through the central channel. Nup358, anchored to the cytoplasmic filaments, stabilizes the capsid at the NPC entry, promoting uncoating and import efficiency, as depletion of either Nup significantly impairs HIV-1 infectivity. This capsid-NPC interaction allows the ~30 nm wide HIV-1 core to navigate the ~40 nm NPC channel, a process adaptive to the pore's flexibility. Influenza A virus employs a distinct export strategy via its non-structural protein 2 (NS2, also called NEP), which binds Nup98 to hijack mRNA export pathways for viral ribonucleoproteins (vRNPs). NS2 contains a leucine-rich NES that interacts with the cellular export factor CRM1, but it also directly associates with the GLFG-repeat domain of Nup98, a peripheral FG-Nup on the nuclear basket, to tether vRNPs and facilitate their passage through the NPC. Overexpression of Nup98's GLFG domain inhibits this interaction, reducing virus propagation by blocking vRNP export. This binding remodels the NPC's export machinery, prioritizing viral over host mRNA, and contributes to the nuclear-to-cytoplasmic relocation of viral genomes during late infection stages. Bacterial pathogens, such as those from genera like Salmonella and Shigella, inject effector proteins via type III secretion systems that mimic NLS or NES motifs to exploit NPC-mediated transport. These effectors, termed nucleomodulins, encode classical or non-classical NLS sequences that bind importins, enabling active translocation through the NPC into the nucleus where they suppress host defenses or alter transcription. For instance, Salmonella effector SpvC contains an NLS that interacts with importin-α/β, docking at FG-Nups for nuclear entry and subsequent manipulation of immune signaling pathways by inactivating MAPKs.^[68] This mimicry allows bacteria to evade cytoplasmic detection and directly reprogram nuclear events, enhancing intracellular survival without disrupting the overall NPC structure. Certain viruses disrupt NPC integrity to accommodate oversized cargoes, with herpes simplex virus 1 (HSV-1) protein ICP27 serving as a key example. ICP27 binds core FG-Nups like Nup62 in the central channel, imposing a selective blockade on host protein import via classical NLS and transportin pathways while promoting viral mRNA export through interactions with the TAP/NXF1 exporter. This binding remodels the FG-Nup hydrogel barrier, increasing pore permeability to facilitate the export of viral RNPs that exceed typical size limits for host cargoes. Consequently, ICP27 expression leads to NPC clustering and altered nucleoporin distribution, optimizing viral replication at the expense of host transport fidelity. For incoming HSV-1, capsids (~125 nm) dock at the NPC cytoplasmic face, allowing genome injection into the nucleus without full capsid transit. Host cells deploy post-translational modifications, such as SUMOylation, to fortify the NPC against pathogen exploitation. SUMOylation of Nups, including RanBP2/Nup358 and Nup153, enhances NPC stability and restricts viral access by altering FG-Nup interactions and promoting antiviral signaling. For example, increased SUMOylation during infection sequesters viral proteins or remodels the NPC to limit HIV-1 or HSV-1 entry, while desumoylating enzymes like SENPs are often targeted by viruses to counteract this defense. This dynamic modification acts as a sensor for nucleocytoplasmic stress, reducing pathogen translocation efficiency and bolstering innate immunity.

Assembly and dynamics

Interphase assembly

During interphase, nuclear pore complexes (NPCs) assemble de novo into the intact nuclear envelope to support nuclear expansion in growing cells, contrasting with the rapid post-mitotic reassembly at the end of mitosis. This process ensures a steady increase in NPC density, maintaining nucleocytoplasmic transport capacity as the nucleus enlarges. Assembly occurs continuously at peripheral chromatin sites, with the nuclear envelope remaining sealed throughout.^[69] The mechanism involves an asymmetric inside-out extrusion of the inner nuclear membrane (INM), where dome-shaped evaginations form and deepen (from 16 nm to 28 nm) before fusing with the outer nuclear membrane (ONM) to create a pore. This bending and fusion are mediated by transmembrane nucleoporins, particularly Pom121 and Ndc1, which anchor early assembly intermediates to the INM and facilitate membrane curvature. Pom121 localizes to the INM early in the process, recruiting subsequent components, while Ndc1 supports pore insertion independent of initial membrane fusion events.^[70]^[71]^[72] According to the prepore model adapted for interphase, cytoplasmic preassembled subcomplexes, such as those containing the Nup107-160 complex (Y-complex), are transported and fuse with a nuclear scaffold to initiate pore formation. Nucleoporin Nup153 plays a pivotal role by binding the INM through its N-terminal amphipathic helix, which prefers high-curvature membranes and drives local bending; this interaction is regulated by RanGTP, which releases transportin-mediated inhibition in the nucleus. Nup153 then recruits the Nup107-160 complex to stabilize the site and promote symmetric scaffold expansion.^[73]^[73] Regulation begins with chromatin-associated factors like ELYS, which binds AT-rich regions and recruits the Nup107-160 complex to potential assembly sites near the nuclear periphery, though ELYS is more critical during post-mitotic phases. In growing vertebrate cells, this results in approximately 60–80 new NPCs forming per nucleus per hour, as observed in live imaging of NRK cells.^[74]^[75]^[69] Evidence for these dynamics comes from high-resolution live-cell imaging, including super-resolution microscopy, which visualizes Nup153-dependent INM evaginations preceding full pore maturation and confirms the inside-out progression over about 100 minutes. These studies highlight Nup153's helix as essential for curvature, with mutants impairing assembly by up to 60%.^[70]^[73]

Mitotic disassembly and reassembly

During mitosis in metazoan cells, the nuclear pore complex (NPC) undergoes complete disassembly to facilitate nuclear envelope breakdown (NEBD), allowing chromosome segregation. This process begins in prophase/prometaphase and is primarily driven by phosphorylation of nucleoporins (Nups) by mitotic kinases, leading to the collapse of the NPC scaffold and loss of nuclear permeability.^[76]^[77] Cyclin-dependent kinase 1 (CDK1) initiates disassembly by hyperphosphorylating scaffold Nups, such as Nup98, which disrupts key interactions within the NPC structure, including those between Nup98 and Nup155. Polo-like kinase 1 (PLK1) then contributes in a stepwise manner, recruiting to phosphorylated intrinsically disordered regions (IDRs) of linker Nups like Nup53 to target the cytoplasmic filaments, central channel, and inner ring, ultimately permeabilizing the nuclear barrier when approximately 60% of Nup98 is removed.^[76] The disassembly occurs in defined stages: early dissociation of the nuclear basket (e.g., Nup153, Tpr) and Y-complex (e.g., Nup107-160) precedes PLK1-dependent breakdown of the inner ring (e.g., Nup93, Nup188) and central channel FG-Nups (e.g., Nup62, Nup98), which disperse into the endoplasmic reticulum (ER) or cytoplasm. Transmembrane Nups, such as POM121 and Ndc1, remain embedded in NE/ER membrane fragments throughout mitosis, providing anchors for later reassembly.^[77]^[76] Reassembly begins in telophase as chromosomes decondense, with dephosphorylation of Nups by protein phosphatases reversing mitotic modifications to enable subcomplex coalescence around chromatin. The Y-complex (Nup107-160) binds chromatin first in early anaphase, followed by transmembrane Nups like POM121 and scaffold components like Nup93; FG-Nups such as Nup98 and Nup62 integrate later to restore transport competence. RanGTP, generated near chromatin, plays a crucial role by displacing importins from Nups, promoting their recruitment and stabilizing interactions during this ordered process.^[77]^[78]^[79] This full disassembly-reassembly cycle is characteristic of metazoans undergoing open mitosis, contrasting with ascomycetes like yeast, where NPCs remain largely intact or undergo only partial disassembly during closed mitosis due to the absence of NEBD.^[80]^[78]

Integrity maintenance

The nuclear pore complex (NPC) maintains its structural integrity through regulated turnover of its constituent nucleoporins (Nups), which varies by subcomplex. Peripheral Nups, particularly those in the cytoplasmic and nuclear basket regions, exhibit relatively rapid turnover with half-lives on the order of days, allowing adaptation to cellular needs.^[5] In contrast, the stable core scaffold Nups, forming the inner ring and transmembrane components, display exceptional longevity with half-lives spanning months to years, contributing to the overall durability of the NPC.^[81] Damaged FG-repeat Nups, which line the central transport channel, are selectively targeted for ubiquitin-mediated proteasomal degradation to prevent aggregation and ensure functional barrier properties.^[82] NPC integrity is further preserved through active repair mechanisms that address membrane defects around the pore. The endosomal sorting complexes required for transport (ESCRT-III) pathway plays a critical role in sealing nuclear envelope (NE) herniations and holes that form near NPCs, particularly those arising from mechanical stress or lipid imbalances.^[83] In yeast, the ESCRT-III subunit Chm7 directly binds phosphatidic acid-enriched regions at the inner NE adjacent to NPCs, facilitating membrane remodeling to restore envelope continuity without disrupting pore function.^[84] This quality control process also surveils aberrant NPC assemblies, promoting their disassembly and clearance to maintain selective transport fidelity.^[82] In organisms undergoing closed mitosis, such as many fungi, NPCs are preserved intact to sustain nuclear envelope continuity throughout the cell cycle. Unlike open mitosis in higher eukaryotes, where NPCs disassemble, fungal NPCs remain embedded in the intact NE, supporting nucleocytoplasmic transport during spindle formation and chromosome segregation within the nucleus.^[85] This preservation mechanism ensures minimal disruption to nuclear integrity, highlighting evolutionary adaptations in mitotic strategies.^[86] Over the cell's lifetime, NPC integrity declines with aging, leading to accumulated damage and impaired function in senescent cells. In postmitotic tissues, prolonged lack of NPC turnover results in structural deterioration, including clustering and loss of Nups, which compromises the selective permeability barrier and causes leaky nucleocytoplasmic transport. This age-related leakage allows aberrant mixing of nuclear and cytoplasmic contents, contributing to cellular dysfunction and reduced homeostasis.^[87]

Biomedical significance

Associated diseases

Dysfunction of the nuclear pore complex (NPC) has been implicated in various human diseases, collectively termed nucleoporinopathies, where mutations in nucleoporin genes lead to impaired nucleocytoplasmic transport and protein aggregation. In amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), mutations or dysregulation of nucleoporins such as NUP62 contribute to the mislocalization of RNA-binding proteins like TDP-43, promoting pathological aggregates in motor neurons.^[88] Similarly, reduced expression of NUP62 and sequestration into TDP-43 aggregates disrupts nuclear import, exacerbating neurodegeneration in C9orf72-linked ALS/FTD cases.^[89] While direct mutations in NUP85 are less commonly reported in ALS/FTD, broader nucleoporin depletion correlates with transport defects and neuronal loss in these disorders.^[90] In certain cancers, nucleoporin gene fusions drive oncogenesis by altering NPC function and signaling. For instance, NUP358 (also known as RanBP2) fusions, such as NUP358-ALK, have been identified in inflammatory myofibroblastic tumors.^[91] Notably, fusions involving NUP98 with various partners, such as HOXA9, are recurrent in acute myeloid leukemia (AML) and promote leukemogenesis through aberrant transcriptional activation and disrupted nuclear transport.^[92] More broadly, such fusions can enhance oncogenic signaling by facilitating aberrant nuclear translocation of transcription factors.^[16] Transport defects mediated by NPC components are targeted therapeutically in hematologic malignancies. CRM1 (exportin 1, XPO1) inhibitors, such as selinexor, block nuclear export of tumor suppressors like p53, showing efficacy in relapsed/refractory acute myeloid leukemia by restoring nucleocytoplasmic homeostasis.^[93] Clinical trials have demonstrated that these selective inhibitors of nuclear export (SINEs) improve progression-free survival when combined with chemotherapy in leukemia patients.^[94] Aging-related neurodegeneration often involves "leaky" NPCs, where age-dependent deterioration increases nuclear permeability, allowing cytoplasmic proteins to invade the nucleus and disrupt gene expression. This NPC breakdown is a hallmark in Alzheimer's disease and ALS, correlating with oxidative damage to nucleoporins and accelerated cognitive decline.^[95] In post-mitotic neurons, such permeability defects contribute to proteostasis failure and tau pathology.^[96] Specific monogenic disorders arise from nucleoporin mutations, including steroid-resistant nephrotic syndrome (SRNS) caused by biallelic variants in NUP93, which impair podocyte function and lead to proteinuria and kidney failure in children.^[97] These NUP93 mutations disrupt NPC assembly, reducing nuclear import efficiency in glomerular cells and causing syndromic features like optic atrophy in some cases.^[98] Viruses exploit NPC transport to promote oncogenesis, as seen in high-risk human papillomavirus (HPV)-associated cancers where the E7 oncoprotein uses its nuclear localization signal (NLS) to enter the nucleus via NPC-mediated import, inactivating Rb and driving cervical carcinogenesis.^[99] This exploitation enhances viral replication and cellular transformation, contributing to HPV-linked malignancies.^[100] Emerging therapeutics target FG-nucleoporins (FG-Nups) and associated importins for cancer treatment, with importin β1 (KPNB1) inhibitors like ivermectin showing preclinical promise in blocking nuclear import of oncoproteins in breast and prostate cancers.^[101] Small molecules disrupting FG-Nup interactions with karyopherins are being developed to selectively impair transport in tumor cells, minimizing effects on normal tissues.^[102]

Evolutionary aspects

The nuclear pore complex (NPC) originated approximately 1.5 billion years ago, contemporaneous with the evolution of the eukaryotic nucleus during the transition from prokaryotic ancestors. This timeline aligns with the emergence of the last eukaryotic common ancestor (LECA), where the modern NPC is believed to have been fully established as a sophisticated transport machinery. Evidence suggests that proto-NPC structures may have arisen from archaea-like ancestors, potentially involving a primordial "protocoatomer" module that organized membrane fenestrations and facilitated early compartmentalization.^[103]^[104]^[10] A core scaffold of the NPC, characterized by eightfold rotational symmetry and composed of at least eight conserved nucleoporins (Nups)—including key components of the Y-complex such as Nup133, Nup107, Seh1, and Nup85—is remarkably preserved across eukaryotic lineages from yeast to humans. This structural conservation underscores the NPC's ancient origin at the LECA, with the inner and outer ring scaffolds maintaining a stable architecture despite sequence-level divergences. In contrast, FG-Nups, which form the selective permeability barrier through their phenylalanine-glycine (FG) repeat domains, have undergone expansion and diversification following the LECA, particularly in multicellular organisms where additional paralogs enhance regulatory functions beyond basic transport.^[105]^[10]^[104] Evolutionary divergences in NPC architecture are evident in specific lineages, reflecting adaptations to diverse cellular environments. For instance, plant NPCs, as seen in species like Arabidopsis thaliana, exhibit asymmetries such as the absence of cytoplasmic filaments and divergent homologs of the basket protein Tpr (NUA in plants), alongside paralogs in the Y-complex that may support specialized transport needs in sessile multicellular life. In trypanosomes like Trypanosoma brucei, significant losses and innovations occur, including the absence of the POM152 ortholog and the presence of unique multi-complex FG-Nups like TbNup109, which contribute to a Ran-dependent mRNA export system distinct from that in opisthokonts. These variations highlight the NPC's plasticity while preserving core transport functionality.^[10]^[105] Functionally, the NPC has evolved from a rudimentary diffusion barrier in early eukaryotes—relying on basic FG-Nup interactions for passive selectivity—to a multifaceted regulator in higher eukaryotes, where expanded FG-Nup repertoires enable intricate control over nucleocytoplasmic trafficking and integration with cellular signaling pathways. This progression parallels increasing organismal complexity, with conserved scaffold elements ensuring structural integrity across ~1.5 billion years of divergence.^[10]^[104]

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