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Components and Regulation of Nuclear Transport Processes Bastien Cautain1*, Richard Hill2,3*, Nuria De Pedro1 and Wolfgang Link2,3

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Components and Regulation of Nuclear Transport Processes Bastien Cautain1*, Richard Hill2,3*, Nuria De Pedro1 and Wolfgang Link2,3 View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Universidade do Algarve REVIEW ARTICLE Components and regulation of nuclear transport processes Bastien Cautain1*, Richard Hill2,3*, Nuria de Pedro1 and Wolfgang Link2,3 1 Fundacion MEDINA Parque tecnologico ciencias de la salud, Granada, Spain 2 Regenerative Medicine Program, Departamento de Ciencias^ Biomedicas e Medicina, Universidade do Algarve, Portugal 3 IBB Institute for Biotechnology and Bioengineering, Centro de Biomedicina Molecular e Estrutural, Universidade do Algarve, Faro, Portugal Keywords The spatial separation of DNA replication and gene transcription in the anti-cancer therapy, anti-viral therapy, nucleus and protein translation in the cytoplasm is a uniform principle of karyopherins, nuclear export, nuclear import, eukaryotic cells. This compartmentalization imposes a requirement for a nuclear pore complex, nuclear trafficking transport network of macromolecules to shuttle these components in and Correspondence out of the nucleus. This nucleo-cytoplasmic transport of macromolecules is W. Link, Department of Biomedical critical for both cell physiology and pathology. Consequently, investigating Sciences and Medicine, University of its regulation and disease-associated alterations can reveal novel therapeu- Algarve, Gambelas Campus, Building 7, tic approaches to fight human diseases, such as cancer or viral infection. Room 3.17, 8005-139 Faro, Portugal The characterization of the nuclear pore complex, the identification of Fax: +351 289 800076 transport signals and transport receptors, as well as the characterization of Tel: +351 289 800094 the Ran system (providing the energy source for efficient cargo transport) E-mail: [email protected] has greatly facilitated our understanding of the components, mechanisms *These authors contributed equally to this and regulation of the nucleo-cytoplasmic transport of proteins in our cells. work Here we review this knowledge with a specific emphasis on the selection of disease-relevant molecular targets for potential therapeutic intervention. (Received 26 August 2014, revised 11 November 2014, accepted 12 November 2014) doi:10.1111/febs.13163 Introduction The deregulation of the nuclear import and export nucleophosmin retinoblastoma, b-catenin, nuclear fac- machinery is a key marker of various diseases [1,2]. For tor-jB (NF-jB), survivin and cyclin D1 [3–5]. Beyond example, many tumor suppressor transcription factors cancer, many viruses including human HIV-1, influenza show cytoplasmic sequestration ablating their nuclear A, dengue, respiratory syncytial virus, rabies, Rift Val- functions allowing, for example, uncontrolled cell divi- ley fever virus and Venezuelan equine encephalitis virus sion [3]. The aberrant localization of onco-proteins can rely on the transport of specific viral proteins into the also lead to their inadequate activation. Examples of host cell nucleus to perturb the anti-viral response. aberrant nucleo-cytoplasmic shuttling that correlates Therefore, inhibiting the nuclear trafficking of viral pro- with tumor formation, progression or resistance to teins has been proposed as a viable therapeutic strategy treatment include p53, FOXO3a, p27, BRCA1, APC, [6]. Over the last decade, the research community has Abbreviations CRM1, exportin1 or Xpo1, chromosome region maintenance 1; EM, electron microscopy; FG, phenylalanineglycine; FG-Nups, phenylalanineglycine nucleoporins; Imp-a, importin-a; Imp-b, importin-b; NE, nuclear envelope; NES, nuclear export signal; NF-jB, nuclear factor-jB; NLS, nuclear localization signal; NPC, nuclear pore complex; NTR, nuclear transport receptor; Nups, nucleoporins; POMs, Pore membrane proteins; PY-NLS, proline-tyrosine NLS. FEBS Journal 282 (2015) 445–462 ª 2014 FEBS 445 Components and regulation of nuclear transport processes B. Cautain et al. acquired a critical mass of significant knowledge on the plasmic side and eight protein filaments on the nuclear constituents of the nuclear transport machinery. The side that converge to a ring-like structure termed the emerging picture, while intriguingly complex, suggests nuclear basket. that there is an availability of a broad range of The NPC is composed of 30 different proteins molecular targets enabling specific therapeutic interven- termed nucleoporins (Nups) [17] that are organized tions. The transport of cargo proteins is mediated by into several sub-complexes, each of which is present in several distinct types of transport signals that are recog- multiple copies, resulting in approximately 500–1000 nized by specific transport receptors or via a variety of individual proteins in the fully assembled NPC [18]. adaptor proteins. These transport receptors can then The transport of salts, nucleotides, small molecules/ interact with components of the nuclear pore complex proteins and components required for the syntheses of (NPC) and with the Ras family GTPase Ran. Many of DNA and RNA occurs passively by diffusion through the steps within this process have the potential to be the NPC. In contrast, proteins larger than 40–65 kDa therapeutically targeted for innovative anti-cancer and must be transported into the nucleus through the NPC anti-viral therapies. with the assistance of transport receptors. These recep- tors recognize the transport signals that are present on The nuclear envelope and the nuclear cargo proteins allowing their import (reviewed in [19]). pore complex The key function of the NPC is to form a diffusion barrier between the cytoplasm and the nuclear com- The nucleus is surrounded by an envelope composed of partment and to enable the nucleo-cytoplasmic traffic two phospholipidic membranes: an outer and an inner of macromolecules. In addition, the NPC is also nuclear membrane that are 30 nm apart. The nuclear involved in other nuclear processes that include DNA envelope (NE) provides a much stronger physical bar- repair [20], the cell cycle [21], chromatin organization rier than the single cordon of the plasma membrane. [22], transcription regulation [23,24], epigenetic mem- The outer nuclear membrane is continuous with the ory [25] and RNA maturation and quality control [26]. endoplasmic reticulum [7], whereas the inner nuclear membrane is associated with a network of intermediate Nucleoporin proteins filaments composed of lamin called the nuclear lamina. This acts as a site of attachment for chromosomes and Despite its enormous dimensions, the NPC is built as a shield for the nucleus [8]. The NE functions like a from a surprisingly small number of proteins called selectively permeable barrier allowing macromolecules nucleoporins (Nups) [18]. The NPC displays a high to move between the nucleus and the cytoplasm via a degree of internal symmetry and can be divided into a gatekeeper, the NPC. The NPC is a huge protein symmetric part, enclosed in the nuclear membrane, complex that fuses the internal and external nuclear and an asymmetric part, with extensions into the membrane to form an aqueous channel (Fig. 1). The nucleus or cytoplasm (Fig. 1). Nups from the symmet- NPC is cylindrical measuring 100–150 nm in diameter ric part of the NPC are generally classified into three and 50–70 nm in thickness [9] and is broadly conserved categories: membrane-anchored (POMs, part of the in eukaryotes [10,11]. The molecular mass of the NPC is nuclear envelope), scaffold (coat Nups and adaptor approximately 125 000 kDa and the number of NPCs Nups) and channel (barrier Nups). Each category has per nucleus is highly variable among organisms. The unique structural features that are essential to execute average number of NPCs within a vertebrate cell is specific functions. The Nups that form the asymmetric between 2000 and 5000 [12] and has been extensively part of the NPC are called nuclear basket Nups and studied by electron microscopy (EM). In particular the cytoplasmic filament Nups. development of cryo-EM and cryo-electron tomography (cryo-ET) allowed structural preservation to be Membrane Nups enhanced and purification steps to be minimized and as a consequence the detailed and artifact-free analysis of Membrane Nups (POMs) anchor the symmetric part the NPC [12–15]. These EM-based studies revealed a of the NPC to the pore membrane where the inner highly modular and dynamic structure with a dough- and outer nuclear membranes fuse to form the nuclear nut-shaped central core with an eightfold rotational pore binding the assembly complex to the NE. Mem- symmetry [16]. A central channel is surrounded by three brane Nups contain transmembrane a-helices that ring-like structures, namely the cytoplasmic ring, the allow the protein to anchor onto the membrane while central spoke ring and the nuclear ring. Attached to this large regions extend toward the luminal and pore sides core structure are eight protein filaments on the cyto- of the membrane [27,28]. 446 FEBS Journal 282 (2015) 445–462 ª 2014 FEBS B. Cautain et al. Components and regulation of nuclear transport processes A B Fig. 1. Overall structure and molecular composition of the nuclear pore complexes (NPCs). (A) General structural features of the NPC. (B) A schematic model of the NPC. In this model, the NPC is divided into several groups according to their location and structural characteristics. The symmetrical core is composed of C membrane-anchored POMS (transmembrane ring), channel Nups (central FG-Nups) and scaffold Nups composed by adaptor Nups (inner and linker Nups) and coat Nups (outer ring). Asymmetric parts of the pore are the nuclear
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