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BBA - Molecular Cell Research (v.1813, #9)
Central role of nuclear transport in signalling, viral infection and development
by David A. Jans (pp. 1561-1561).
Molecular basis for specificity of nuclear import and prediction of nuclear localization by Mary Marfori; Andrew Mynott; Jonathan J. Ellis; Ahmed M. Mehdi; Neil F.W. Saunders; Paul M. Curmi; Jade K. Forwood; Boden Mikael Bodén; Bostjan Kobe (pp. 1562-1577).
Although proteins are translated on cytoplasmic ribosomes, many of these proteins play essential roles in the nucleus, mediating key cellular processes including but not limited to DNA replication and repair as well as transcription and RNA processing. Thus, understanding how these critical nuclear proteins are accurately targeted to the nucleus is of paramount importance in biology. Interaction and structural studies in the recent years have jointly revealed some general rules on the specificity determinants of the recognition of nuclear targeting signals by their specific receptors, at least for two nuclear import pathways: (i) the classical pathway, which involves the classical nuclear localization sequences (cNLSs) and the receptors importin-α/karyopherin-α and importin-β/karyopherin-β1; and (ii) the karyopherin-β2 pathway, which employs the proline-tyrosine (PY)-NLSs and the receptor transportin-1/karyopherin-β2. The understanding of specificity rules allows the prediction of protein nuclear localization. We review the current understanding of the molecular determinants of the specificity of nuclear import, focusing on the importin-α•cargo recognition, as well as the currently available databases and predictive tools relevant to nuclear localization. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.
Keywords: Importin-α/karyopherin-α; Importin-β/karyopherin-β1; Nuclear localization; Nuclear localization sequence (NLS); Nucleo-cytoplasmic transport; Prediction of nuclear localization; Transportin-1/karyopherin-β2
The importin β binding domain as a master regulator of nucleocytoplasmic transport by Kaylen Lott; Gino Cingolani (pp. 1578-1592).
Specific and efficient recognition of import cargoes is essential to ensure nucleocytoplasmic transport. To this end, the prototypical karyopherin importin β associates with import cargoes directly or, more commonly, through import adaptors, such as importin α and snurportin. Adaptor proteins bind the nuclear localization sequence (NLS) of import cargoes while recruiting importin β via an N-terminal importin β binding (IBB) domain. The use of adaptors greatly expands and amplifies the repertoire of cellular cargoes that importin β can efficiently import into the cell nucleus and allows for fine regulation of nuclear import. Accordingly, the IBB domain is a dedicated NLS, unique to adaptor proteins that functions as a molecular liaison between importin β and import cargoes. This review provides an overview of the molecular role played by the IBB domain in orchestrating nucleocytoplasmic transport. Recent work has determined that the IBB domain has specialized functions at every step of the import and export pathway. Unexpectedly, this stretch of ~40 amino acids plays an essential role in regulating processes such as formation of the import complex, docking and translocation through the nuclear pore complex (NPC), release of import cargoes into the cell nucleus and finally recycling of import adaptors and importin β into the cytoplasm. Thus, the IBB domain is a master regulator of nucleocytoplasmic transport, whose complex molecular function is only recently beginning to emerge. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.► The IBB domain functions as a specialized NLS. ► The nature of the IBB domain influences importin β avidity for nucleoporins. ► The IBB regulates import complex disassembly, and karyopherin recycling.
Keywords: IBB; Importin β binding domain; NLS; nuclear localization sequence; NPC; nuclear pore complex; Nuclear import; Karyopherins; Importin β; Importin α; Ran
Nuclear import by karyopherin-βs: Recognition and inhibition by Yuh Min Chook; Suel Katherine E. Süel (pp. 1593-1606).
Proteins in the karyopherin-β family mediate the majority of macromolecular transport between the nucleus and the cytoplasm. Eleven of the 19 known human karyopherin-βs and 10 of the 14 S. cerevisiae karyopherin-βs mediate nuclear import through recognition of nuclear localization signals or NLSs in their cargos. This receptor-mediated process is essential to cellular viability as proteins are translated in the cytoplasm but many have functional roles in the nucleus. Many known karyopherin-β-cargo interactions were discovered through studies of the individual cargos rather than the karyopherins, and this information is thus widely scattered in the literature. We consolidate information about cargos that are directly recognized by import-karyopherin-βs and review common characteristics or lack thereof among cargos of different import pathways. Knowledge of karyopherin-β-cargo interactions is also critical for the development of nuclear import inhibitors and the understanding of their mechanisms of inhibition. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.►Karyopherin-β (Kapβ) proteins transports protein cargos into the nucleus. ►Kapβs recognize nuclear localization signals or NLSs in their cargos. ►Of the 19 human Kapβs only two have well characterized NLSs. ►Many NLSs recognized by individual Kapβs are large and diverse in sequence. ►New approaches are needed to classify diverse NLSs recognized by most Kapβs.
Keywords: Karyopherin; Importin; Transportin; Nuclear localization signal; Classical-NLS; PY-NLS; Nuclear pore complex; Nuclear localization; Nuclear import; NLS
Single molecule studies of nucleocytoplasmic transport by Li-Chun Tu; Siegfried M. Musser (pp. 1607-1618).
Molecular traffic between the cytoplasm and the nucleoplasm of eukaryotic cells is mediated by nuclear pore complexes (NPCs). Hundreds, if not thousands, of molecules interact with and transit through each NPC every second. The pore is blocked by a permeability barrier, which consists of a network of intrinsically unfolded polypeptides containing thousands of phenylalanine–glycine (FG) repeat motifs. This FG-network rejects larger molecules and admits smaller molecules or cargos bound to nuclear transport receptors (NTRs). For a cargo transport complex, minimally consisting of a cargo molecule plus an NTR, access to the permeability barrier is provided by interactions between the NTR and the FG repeat motifs. Numerous models have been postulated to explain the controlled accessibility and the transport characteristics of the FG-network, but the amorphous, flexible nature of this structure has hindered characterization. A relatively recent development is the ability to monitor the real-time movement of single molecules through individual NPCs via single molecule fluorescence (SMF) microscopy. A major advantage of this approach is that it can be used to continuously monitor a series of specific molecular interactions in an active pore with millisecond time resolution, which therefore allows one to distinguish between kinetic and thermodynamic control. Novel insights and prospects for the future are outlined in this review. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.► Diffusion through nuclear pores can be imaged with millisecond time resolution. ► Single molecule behavior is explained by diffusion models. ► Single molecule fluorescence is a powerful tool for understanding nuclear transport.
Keywords: Abbreviations; NPC; nuclear pore complex; Nup; nucleoporin; NE; nuclear envelope; SMF; single molecule fluorescence; NTR; nuclear transport receptor; S/N; signal-to-noise ratio; fps; frames per second; smFRET; single molecule fluorescence resonance energy transferNuclear pore complex; Nuclear transport; Single molecule fluorescence
The MAPK cascades: Signaling components, nuclear roles and mechanisms of nuclear translocation by Alexander Plotnikov; Eldar Zehorai; Shiri Procaccia; Rony Seger (pp. 1619-1633).
The MAPK cascades are central signaling pathways that regulate a wide variety of stimulated cellular processes, including proliferation, differentiation, apoptosis and stress response. Therefore, dysregulation, or improper functioning of these cascades, is involved in the induction and progression of diseases such as cancer, diabetes, autoimmune diseases, and developmental abnormalities. Many of these physiological, and pathological functions are mediated by MAPK-dependent transcription of various regulatory genes. In order to induce transcription and the consequent functions, the signals transmitted via the cascades need to enter the nucleus, where they may modulate the activity of transcription factors and chromatin remodeling enzymes. In this review, we briefly cover the composition of the MAPK cascades, as well as their physiological and pathological functions. We describe, in more detail, many of the important nuclear activities of the MAPK cascades, and we elaborate on the mechanisms of ERK1/2 translocation into the nucleus, including the identification of their nuclear translocation sequence (NTS) binding to the shuttling protein importin7. Overall, the nuclear translocation of signaling components may emerge as an important regulatory layer in the induction of cellular processes, and therefore, may serve as targets for therapeutic intervention in signaling-related diseases such as cancer and diabetes. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.► The components and nature of the various MAPK cascade. ► Nuclear functions of the ERK as well as JNK and p38 MAPKs. ► Mechanisms of nuclear translocation of MAPKs.
Keywords: MAPK; ERK1/2; JNK; p38; ERK5; Nuclear translocation
How viruses access the nucleus by Sarah Cohen; Shelly Au; Pante Nelly Panté (pp. 1634-1645).
Many viruses depend on nuclear proteins for replication. Therefore, their viral genome must enter the nucleus of the host cell. In this review we briefly summarize the principles of nucleocytoplasmic transport, and then describe the diverse strategies used by viruses to deliver their genomes into the host nucleus. Some of the emerging mechanisms include: (1) nuclear entry during mitosis, when the nuclear envelope is disassembled, (2) viral genome release in the cytoplasm followed by entry of the genome through the nuclear pore complex (NPC), (3) capsid docking at the cytoplasmic side of the NPC, followed by genome release, (4) nuclear entry of intact capsids through the NPC, followed by genome release, and (5) nuclear entry via virus-induced disruption of the nuclear envelope. Which mechanism a particular virus uses depends on the size and structure of the virus, as well as the cellular cues used by the virus to trigger capsid disassembly and genome release. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.► Many viruses must access the nucleus of the host cell. ► Five strategies have been identified for viral nuclear access. ► These involve waiting for mitosis or using the host nuclear transport machinery. ► A newly identified strategy involves disrupting the nuclear envelope. ► The strategy used depends on the size and structure of the virus.
Keywords: Abbreviations; AAV2; adeno-associated virus 2; AcMNPV; Autographa californica; multiple-capsid nucleopolyhedrovirus; cNLS; classical nuclear localization sequence; cPPT; central polypurine tract; CPV; canine parvovirus; ER; endoplasmic reticulum; EM; electron microscopy; GDP; guanosine diphosphate; GTP; guanosine triphosphate; GV; Granulovirus; HBV; hepatitis B virus; HIV-1; human immunodeficiency virus 1; HSV-1; herpes simplex virus 1; INM; inner nuclear membrane; MLV; murine leukemia virus; MVM; minute virus of mice; NE; nuclear envelope; NLS; nuclear localization sequence; NP; nucleoprotein; NPC; nuclear pore complex; NPV; Nucleopolyhedrovirus; Nup; Nucleoporin or NPC protein; ONM; outer nuclear membrane; PIC; pre-integration complex; RNAi; RNA interference; SV40; simian virus 40; vRNP; viral ribonucleoprotein complexNuclear import; Nuclear pore complex; Viral nuclear import; Virus; Virology
Strategies to inhibit viral protein nuclear import: HIV-1 as a target by Aviad Levin; Abraham Loyter; Michael Bukrinsky (pp. 1646-1653).
Nuclear import is a critical step in the life cycle of HIV-1. During the early (preintegration) stages of infection, HIV-1 has to transport its preintegration complex into the nucleus for integration into the host cell chromatin, while at the later (postintegration) stages viral regulatory proteins Tat and Rev need to get into the nucleus to stimulate transcription and regulate splicing and nuclear export of subgenomic and genomic RNAs. Given such important role of nuclear import in HIV-1 life cycle, this step presents an attractive target for antiviral therapeutic intervention. In this review, we describe the current state of our understanding of the interactions regulating nuclear import of the HIV-1 preintegration complex and describe current approaches to inhibit it. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.► Nuclear import is critical for HIV replication in both dividing and non-dividing cells. ► Nuclear import of the viral pre-integration complex is tightly linked to viral uncoating. ► HIV relies on cellular nuclear import machinery for transporting its pre-integration complex into the nucleus. ► The use of cellular nuclear import pathways by HIV may change depending on cell type or cell activation state. ► Different PIC proteins may regulate nuclear import under different circumstances.
Keywords: HIV-1; Nuclear import; Pre-integration complex; Importins; Nuclear localization signal; Peptides; Small molecule inhibitors
Karyopherins in nuclear transport of homeodomain proteins during development by Wenduo Ye; Wenbo Lin; Alan M. Tartakoff; Tao Tao (pp. 1654-1662).
Homeodomain proteins are crucial transcription factors for cell differentiation, cell proliferation and organ development. Interestingly, their homeodomain signature structure is important for both their DNA-binding and their nucleocytoplasmic trafficking. The accurate nucleocytoplasmic distribution of these proteins is essential for their functions. We summarize information on (a) the roles of karyopherins for import and export of homeoproteins, (b) the regulation of their nuclear transport during development, and (c) the corresponding complexity of homeoprotein nucleocytoplasmic transport signals. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.► Multiple karyopherins play roles in nuclear transport of homeoproteins. ► Nuclear transport of homeoproteins is regulated by different mechanisms in development. ► The corresponding complexity of homeoprotein nucleocytoplasmic transport signals is proposed in this review.
Keywords: Homeodomain; Homeoprotein; Nuclear transport; Importin α; Karyopherin β; NLS; NES; Development; Regulation
HuR and myogenesis: Being in the right place at the right time by Christopher von Roretz; Pascal Beauchamp; Sergio Di Marco; Imed-Eddine Gallouzi (pp. 1663-1667).
The process of muscle cell differentiation into myotubes, termed myogenesis, depends on a complex coordination of myogenic factors, many of which are regulated post-transcriptionally. HuR, an mRNA-binding protein, is responsible for regulating the expression of several such myogenic factors by stabilizing their mRNAs. The critical role for HuR in myogenesis also involves the nucleocytoplasmic shuttling ability of this protein. Indeed, in order to perform its stabilizing functions, HuR must accumulate in the cytoplasm. This requires its dissociation from the import factor Transportin 2 (TRN2) which is actually caused by the cleavage of a portion of cytoplasmic HuR. In this review, we describe the roles of HuR during myogenesis, and the mechanisms regulating its cytoplasmic accumulation. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.► Post-transcriptional regulation of myogenesis involves RNA-binding proteins such as HuR. ► The cytoplasmic accumulation of HuR is required for its pro-myogenic function. ► Caspase-mediated cleavage of HuR promotes its translocation to the cytoplasm. ► A non-cleavable mutant of HuR acts as a dominant-negative that inhibits myogenesis.
Keywords: Abbreviations; TRN2; Transportin 2; ARE; A/U-rich element; AUBP; ARE-binding protein; AMD; ARE-mediated decay; MRF; myogenic regulatory factor; CP; cleavage product; AP; antennepedia; GST; glutathione-; S; -transferase; IP; immunoprecipitation; IF; immunofluorescence; SEM; standard error of the meanHuR; Myogenesis; Transportin 2; Caspase; Myogenic regulatory factor
Expression of nucleocytoplasmic transport machinery: Clues to regulation of spermatogenic development by Andrew T. Major; Penny A.F. Whiley; Kate L. Loveland (pp. 1668-1688).
Spermatogenesis is one example of a developmental process which requires tight control of gene expression to achieve normal growth and sustain function. This review is based on the principle that events in spermatogenesis are controlled by changes in the distribution of proteins between the nuclear and cytoplasmic compartments. Through analysis of the regulated production of nucleocytoplasmic transport machinery in mammalian spermatogenesis, this review addresses the concept that access to the nucleus is tightly controlled to enable and prevent differentiation. A broad review of nuclear transport components is presented, outlining the different categories of machinery required for import, export and non-nuclear functions. In addition, the complexity of nomenclature is addressed by the provision of a concise yet comprehensive listing of information that will aid in comparative studies of different transport proteins and the genes which encode them. We review a suite of existing transcriptional analyses which identify common and distinct patterns of transport machinery expression, showing how these can be linked with key events in spermatogenic development. The additional importance of this for human fertility is considered, in light of data that identify which importin and nuclear transport machinery components are present in testicular cancer specimens, while also providing an indication of how their presence (and absence) may be considered as potential mediators of oncogenesis. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.► Nucleocytoplasmic transport machinery synthesis is regulated during spermatogenesis. ► Particular nucleocyotoplasmic transport machinery is differentially produced as testis cancer progresses. ► The role of regulated nuclear access in development can be tested with existing databases.
Keywords: Abbreviations; NE; Nuclear envelope; NPC; Nuclear pore complex; NUPs; Nucleoporins; NLS; Nuclear localisation signal; cNLS; Classical nuclear localisation signal; NES; Nuclear export signal; IBB; Importin beta binding; RAN-GTP; RAN, in its GTP bound form; RAN-GDP; RAN, in its GDP bound form; SEM; Standard error of the mean; GEO; Gene expression omnibus; TGFβ; Transforming growth factor beta; miRNAs; Micro RNAs; SRY; Sex determining region on the Y chromosome; LMB; Leptomycin BSpermatogenesis; Testis; Importin; Exportin; Karyopherin; Nuclear transport