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The nuclear pore complex: bridging nuclear transport and gene regulation

Nature Reviews Molecular Cell Biology volume 11, pages 490–501 (2010)Cite this article

Subjects

Key Points

  • The nuclear pore complex (NPC) mediates transport of all macromolecules between the nucleus and the cytoplasm. The structure of the NPC — a cylindrical ring-like structure lined with nucleoporins capable of binding to transport factors — governs its transport function.

  • Although transport is the primary function of the NPC, recent research has revealed that the NPC plays an important part in cellular functions taking place on either side of the nuclear envelope.

  • The nuclear basket is a distinct structure extending from the NPC into the nucleus. It is thought to have a role in many different functions, such as transcriptional control, small ubiquitin-related modifier (SUMO) homeostasis, cell cycle progression, chromatin organization and RNA biogenesis.

  • The basket seems to recruit and retain actively transcribed genes to the pore while excluding silenced heterochromatin from the transport channel. This mechanism would ensure efficient transport of messenger ribonucleoproteins (mRNPs) into the cytoplasm, in a manner similar to what was proposed in the 'gene gating hypothesis'.

  • Multiple components involved in the recruitment of active genes to the NPC also have a role in the proper processing, surveillance and export of mRNPs.

  • The cytoplasmic filaments of the NPC interact with the protein synthesis machinery and the cytoskeleton. They are thought to be involved in mediating the release of shuttling proteins from mRNPs, terminating transport and readying the cargo for further engagement in the cytoplasm.

  • Most nuclear and cytoplasmic functions of the NPC seem to increase the efficiency and integration of transport into the broader milieu of the cell.

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.

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Figure 1: Nuclear pore complex structure.
Figure 2: The nuclear pore complex functions as a 'virtual gate'.
Figure 3: The function of the nuclear pore complex peripheral structures.
Figure 4: The gene expression path traverses the NPC.

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Acknowledgements

We are indebted to J. Luban (University of Geneva, Switzerland) for unwavering support to the first author throughout the course of this work. We wish to thank O. Petrini and M. Tonolla (Istituto Cantonale di Microbiologia, Bellinzona, Switzerland) for active hospitality and encouragement. We are grateful to J. Luban, K. Mullin and M. Eisenstein for critical reviewing of the manuscript. We apologize to those colleagues whose primary reference we have not been able to cite owing to space limitations. M.P.R. and C. S.-D.-C. gratefully acknowledge funding they received from the European Commission 7th Framework Programme for Scientific Research (Project number: HEALTH-2007-2.3.2, GA number: HEALTH-F3-2008-201,032 to C. S.-D.-C.) from the National Institutes of Health (R01 GM062427 and R01 GM071329 to M. P. R.) and the American Cancer Society (RSG0404251 to M. P. R. and C. S.-D.-C.).

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  1. Department of Microbiology and Molecular Medicine, University of Geneva, 1 Rue Michel Servet, CH-1211, Geneva, Switzerland

    Caterina Strambio-De-Castillia

  2. Laboratory of Cellular and Structural Biology, The Rockefeller University, 1230 York Avenue, 10065, New York, USA

    Caterina Strambio-De-Castillia & Michael P. Rout

  3. Department of Systems Biology, Center for Cell Decision Processes, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Mario Niepel

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Glossary

Nuclear periphery

The region of the nucleus comprised of the nuclear envelope and its associated structures, including the NPC and the nuclear components found in the neighbourhood.

β-Propeller

A compact structural protein domain of similarly sized β-sheets, which are stacked into a cylinder to resemble the blades of a propeller.

α-Solenoid

A structural protein domain composed of numerous pairs of antiparallel α-helices that are stacked to form a solenoid.

LEM domain

(LAP2, emerin and MAN1 domain). A domain that is present in a family of evolutionarily conserved integral membrane proteins of the INM, which participate in chromatin organization, gene expression regulation and nuclear envelope biogenesis.

SUN domain

(Sad1 and UNC84 domain). A conserved C-terminal amino acid sequence found in integral membrane proteins of the INM. These proteins act with members of the KASH domain-containing protein family to form a molecular 'velcro', which is thought to mediate several processes requiring nuclear repositioning, such as fertilization, establishment of polarity, division and differentiation.

Brownian motion

The seemingly random movement of particles suspended in a liquid or gas, which is driven by the kinetic energy of the particles in the system.

Heterochromatin

A highly condensed form of chromatin that is either genetically inactive or transcriptionally repressed. It is predominantly located near the nuclear envelope and includes centromeres, telomeres and silenced genes.

SUMO homeostasis

The overall level of proteins modified by the covalent attachment of SUMO. It is balanced through the regulated activities of sumoylating ligases and desumoylating proteases.

TRAMP complex

(Trf4 or Trf5, Air1 or Air2 and Mtr4 polyadenylation complex). A protein complex that functions in RNA processing, degradation and surveillance. It polyadenylates various aberrant nuclear RNAs and thus labels them for processing or degradation by the exosome complex.

Exosome complex

A complex of several exonucleases arranged in a ring structure that, assisted by RNA helicases, degrade RNAs in the nucleus and cytoplasm.

SAGA histone acetyltransferase complex

(Spt, Ada, Gcn5 and acetyltransferase histone acetyltransferase complex). A large and highly conserved multiprotein complex required for the normal transcription of many genes.

TREX2 complex

(Transcription–export complex 2). TREX2 comprises Thp1, Sac3, Cdc31 and the Sus1 subunit of the SAGA complex involved in chromatin remodelling and transcriptional activation. TREX2 interacts with the NPC and is thought to have an important role in coupling SAGA-dependent gene expression to mRNA export.

THO complex

A multiprotein complex conserved among yeast and metazoans that is involved in mRNP biogenesis and export. In S. cerevisiae it consists of Hpr1, Mft1, Tho2 and Thp2. The human counterpart consists of the THO complex proteins THOC1–THOC7.

TREX complex

(Transcription–export complex). A complex that consists of components of the THO complex together with Yra1 (homologous to human THOC4) and Sub2 (homologous to human BAT1). The TREX complex interacts with the NPC through the non-Kap NTFs Mex67 and Mtr2, helping to anchor active genes to the nuclear periphery.

Gene gating hypothesis

The hypothesis in which “the nuclear pore complexes are envisioned to serve as gene-gating organelles capable on interacting specifically with expanded (transcribable) portions of the genome”49.

Spindle pole body (SPB)

The only microtubule organizing centre found in S. cerevisiae. SPBs are embedded in the nuclear envelope throughout the yeast life cycle and their functions include chromosome segregation during mitosis and meiosis, and intracellular trafficking.

Spindle assembly checkpoint (SAC)

The SAC monitors the correct attachment of kinetochores to spindle microtubules before anaphase. Unattached kinetochores activate this checkpoint and cause cell-cycle arrest through the inhibition of the anaphase-promoting complex.

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Strambio-De-Castillia, C., Niepel, M. & Rout, M. The nuclear pore complex: bridging nuclear transport and gene regulation. Nat Rev Mol Cell Biol 11, 490–501 (2010). https://doi.org/10.1038/nrm2928

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