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The Nuclear Pore Complex: Bridging Nuclear Transport and Gene Regulation

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The Nuclear Pore Complex: Bridging Nuclear Transport and Gene Regulation REVIEWS The nuclear pore complex: bridging nuclear transport and gene regulation Caterina Strambio-De-Castillia*‡, Mario Niepel§ and Michael P. Rout‡ Abstract | Although the nuclear pore complex (NPC) is best known for its primary function as the key regulator of molecular traffic between the cytoplasm and the nucleus, a growing body of experimental evidence suggests that this structure participates in a considerably broader range of cellular activities on both sides of the nuclear envelope. Indeed, the NPC is emerging as an important regulator of gene expression through its influence on the internal architectural organization of the nucleus and its apparently extensive involvement in coordinating the seamless delivery of genetic information to the cytoplasmic protein synthesis machinery. Nuclear periphery Subcellular compartmentalization by membrane systems, of asymmetrical filamentous structures that connect The region of the nucleus such as the nuclear envelope or the endoplasmic reticu- the NPC core structure to its molecular milieu either comprised of the nuclear lum (ER), pre-dates the emergence of the major modern inside the nucleus or in the cytoplasm (FIG. 3). Within the envelope and its associated eukaryotic lineages (reviewed in REF. 1). Although this nucleus, the nuclear basket structure (hereafter referred structures, including the NPC and the nuclear components adaptation offers advantages, such as allowing cellular to as the basket) connects the NPC to aspects of nuclear found in the neighbourhood. functions to be separated in specialized organelles and metabolism, such as mRNA biogenesis and genome affording more complex means of functional regulation, maintenance. On the opposite side of the membrane, it also poses considerable logistical challenges made specialized filaments project out towards the cytoplasm necessary by the need to exchange material between and channel export cargo towards the protein synthesis separate organelles. The nuclear envelope separates the machinery while funneling incoming cargo from the cellular genome from the rest of the cell and is composed cytoskeleton towards the nuclear interior (FIG.1). of two distinct membranes, the nucleoplasm-facing Work in recent years has caused the field to re- inner nuclear membrane and the cytoplasm-facing outer evaluate the view of the NPC as an insular entity, the nuclear membrane, that are separated by a perinuclear only role of which is nucleocytoplasmic transport. In lumenal space. Traffic between the nucleus and the fact, the NPC seems to be the central unit of a network cytoplasm is accomplished through specialized, circular of proteins and ribonucleoproteins (RNPs) positioned apertures that occur at sites where the inner and outer along the gene expression ‘path’ (FIG. 3). This network *Department of Microbiology and Molecular Medicine, nuclear membranes join together. These apertures are spreads from the basket into a region commonly referred University of Geneva, filled with cylindrical macromolecular assemblies termed to as the nuclear periphery and interconnects neighbour- 1 Rue Michel Servet, nuclear pore complexes (NPCs). ing NPCs to form a multifunctional platform beneath CH-1211 Geneva, NPCs, with a molecular mass of ~50 mDa, are among the nucleoplasmic side of the nuclear envelope. Here, Switzerland. the largest proteinaceous assemblies in the cell and are unique sets of macro molecular complexes assemble to ‡Laboratory of Cellular and Structural Biology, constructed of multiple copies of ~30 different proteins ensure the efficient control of gene expression at the The Rockefeller University, called nucleoporins (Nups). The structure of the NPC transcriptional and post-transcriptional levels (reviewed 1230 York Avenue, consists of two main functional regions: the NPC central in REFS 2,3). On the cytoplasmic side, filaments extend New York, 10065, USA. structure, which is embedded in the plane of the nuclear from the NPC and connect to the protein synthesis §Center for Cell Decision Processes, Department of envelope, and the NPC peripheral structures, which machinery and the cytoskeleton to facilitate the close Systems Biology, Harvard extend the reach of the NPC towards both the nuclear coupling between messenger RNP (mRNP) export and Medical School, Boston, interior and the cytoplasm (FIG. 1). The NPC centre con- translation initiation. This network of protein–protein Massachusetts 02115, USA. sists of an eight-fold symmetrical cylindrical assembly, and protein–RNA interactions is required for the cor- Correspondence to M. R. and which encases the main nuclear transport channel and rect flow of information into and out of the nucleus, and C.S.-D.-C. e-mails: [email protected]; functions as a molecular sieve to regulate the bidirec- ensures that nuclear cargoes can carry out their func- [email protected] tional transport of macromolecules and small meta- tion on both sides of the nuclear envelope with as little doi:10.1038/nrm2928 bolites (FIG. 2). The peripheral NPC extensions consist impediment as possible along their route (FIG. 3). 490 | JULY 2010 | VOLUME 11 www.nature.com/reviews/molcellbio © 2010 Macmillan Publishers Limited. All rights reserved REVIEWS Cytoplasmic FG Nups and filaments Spoke Yeast: Vertebrate: Cytoplasmic filament Cytoplasm NUP358 Central tube Nup159 NUP214 Nup42 NLP1 ONM Transmembrane ring Nups Nuclear envelope Yeast: Vertebrate: INM Pom152 GP210 Pom34 Outer ring Nups Ndc1 NDC1 Nucleoplasm POM121 Yeast: Vertebrate: Basket Nup133 NUP133 Central FG Nups Nup120 NUP160 Yeast: Vertebrate: Nuclear FG Nups and Inner ring Nups Nup145C NUP96 Nup145N NUP98 the basket Yeast: Vertebrate: Nup85 NUP75 Nup116 Yeast: Vertebrate: Nup192 NUP205 Nup84 NUP107 Nup100 Nup60 NUP153 Nup188 NUP188 Seh1 SEH1 Nsp1 NUP62 Nup1 Linker Nups Nup170 NUP155 Sec13 SEC13 Nup57 NUP54 Nup2 Yeast: Vertebrate: Nup157 NUP43 Nup49 NUP58 and Mlp1 TPR Nic96 NUP93 Nup53 NUP35 NUP37 NUP45 Mlp2 Nup82 NUP88 Nup59 Aladin Core scaffold Nups Figure 1 | Nuclear pore complex structure. Each nuclear pore complex (NPC) is a cylindrical structure comprised of eight spokes surrounding a central tube that connects the nucleoplasm and cytoplasm. The outer and inner nuclear membranes (ONM and INM, respectively) of the nuclear envelope join to form grommetsNatur ine which Reviews the | Mol NPCecular sits. TheCell NPCBiolog y is anchored to the nuclear envelope by a transmembrane ring structure that connects to the core scaffold and comprises inner ring and outer ring elements. Linker nucleoporins (Nups) help anchor the Phe-Gly (FG) Nups such that they line and fill the central tube. NPC-associated peripheral structures consist of cytoplasmic filaments, the basket and a distal ring. The Nups that are known to constitute each NPC substructure are listed, with yeast and vertebrate homologues indicated. Both inner and outer ring Nups are known to form biochemically stable NPC subcomplexes, which are thought to have a role in NPC biogenesis and nuclear envelope assembly. GP210, glycoprotein 210; Mlp, myosin-like protein; Ndc1, nuclear division cycle protein 1; Nic96, Nup-interacting component of 76 kDa; NLP1, Nup-like protein 1; Pom, pore membrane protein; Seh1, SEC13 homologue 1; TPR, translocated promoter region. In this Review, we discuss apparent points of integra- that combined proteomic, biophysical and imaging tion between the NPC and the greater cellular environ- data7,8. This map agrees with a large body of comple- ment, and explore the emerging role of this complex mentary data in both vertebrates and yeast (reviewed in the coordination of diverse nuclear and cytoplasmic in REF. 9) and allows each Nup to be assigned to par- processes beyond transport. ticular substructures in the NPC. Nups can thus be sub- divided into four classes (FIG. 1): transmembrane, core Structure of the NPC scaffold (inner ring and outer ring), linker and Phe-Gly The morphology of the NPC was first studied in detail (FG). In yeast and vertebrates, three transmembrane in vertebrates, although it seems that most features Nups span the pore membrane and constitute an outer are conserved throughout eukaryotes4. The vertebrate transmembrane ring (also known as the lumenal ring) NPC consists of a ~125-nm diameter core structure, that anchors the NPC to the nuclear envelope. Around which contains eight spokes in a radially symmetrical a dozen core scaffold Nups form the outer and inner arrangement. The spokes join to form three main rings rings, which together comprise the core scaffold of the surrounding a central tube (FIG. 1). The inner ring (also NPC. This scaffold encases the central transport tube known as the inner spoke ring or central ring) at the of the NPC and is formed from several biochemically NPC’s equator is sandwiched between two outer rings, stable and conserved NPC subcomplexes that seem to one on the cytoplasmic side and one on the nucleo- have a key role as building blocks during NPC biogenesis plasmic side, with each ring closely following the curved (for example, the conserved Saccharomyces cerevisiae inner surface of the pore membrane (FIG. 1). This triple- Nup84 and Nup170 complexes and their respective ring framework of the NPC creates a central channel metazoan homologues, the NUP170–NUP160, and the with a minimum diameter of ~35 nm, which has been NUP35–NUP155 complexes)10–12. Anchored to the core inferred mainly from the size of artificial transport scaffold are a dozen largely unfolded FG Nups, which cargo (reviewed in REFS 5,6). line the surface
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