scholarly journals The Viral Capsid: A Master Key to Access the Host Nucleus

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1178
Author(s):  
Guillermo Blanco-Rodriguez ◽  
Francesca Di Nunzio
Keyword(s):  
Nuclear Transport ◽  
Viral Capsid ◽  
Nuclear Pore ◽  
Nuclear Entry ◽  
Dna Viruses ◽  
Dividing Cells ◽  
Cellular Machinery ◽  
Cellular Defenses ◽  
Main Components ◽  
And Function

Viruses are pathogens that have evolved to hijack the cellular machinery to replicate themselves and spread to new cells. During the course of evolution, viruses developed different strategies to overcome the cellular defenses and create new progeny. Among them, some RNA and many DNA viruses require access to the nucleus to replicate their genome. In non-dividing cells, viruses can only access the nucleus through the nuclear pore complex (NPC). Therefore, viruses have developed strategies to usurp the nuclear transport machinery and gain access to the nucleus. The majority of these viruses use the capsid to manipulate the nuclear import machinery. However, the particular tactics employed by each virus to reach the host chromatin compartment are very different. Nevertheless, they all require some degree of capsid remodeling. Recent notions on the interplay between the viral capsid and cellular factors shine new light on the quest for the nuclear entry step and for the fate of these viruses. In this review, we describe the main components and function of nuclear transport machinery. Next, we discuss selected examples of RNA and DNA viruses (HBV, HSV, adenovirus, and HIV) that remodel their capsid as part of their strategies to access the nucleus and to replicate.

scholarly journals The Role of Capsid in HIV-1 Nuclear Entry

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1425
Author(s):  
Anabel Guedán ◽  
Eve R. Caroe ◽  
Genevieve C. R. Barr ◽  
Kate N. Bishop
Keyword(s):  
Nuclear Pore ◽  
Outer Face ◽  
Nuclear Entry ◽  
Nuclear Compartment ◽  
Critical Step ◽  
Technological Advances ◽  
Dividing Cells ◽  
Hiv 1 ◽  
Gain Access

HIV-1 can infect non-dividing cells. The nuclear envelope therefore represents a barrier that HIV-1 must traverse in order to gain access to the host cell chromatin for integration. Hence, nuclear entry is a critical step in the early stages of HIV-1 replication. Following membrane fusion, the viral capsid (CA) lattice, which forms the outer face of the retroviral core, makes numerous interactions with cellular proteins that orchestrate the progress of HIV-1 through the replication cycle. The ability of CA to interact with nuclear pore proteins and other host factors around the nuclear pore determines whether nuclear entry occurs. Uncoating, the process by which the CA lattice opens and/or disassembles, is another critical step that must occur prior to integration. Both early and delayed uncoating have detrimental effects on viral infectivity. How uncoating relates to nuclear entry is currently hotly debated. Recent technological advances have led to intense discussions about the timing, location, and requirements for uncoating and have prompted the field to consider alternative uncoating scenarios that presently focus on uncoating at the nuclear pore and within the nuclear compartment. This review describes recent advances in the study of HIV-1 nuclear entry, outlines the interactions of the retroviral CA protein, and discusses the challenges of investigating HIV-1 uncoating.

scholarly journals The HIV-1 capsid core is an opportunistic nuclear import receptor

2021 ◽  
Author(s):  
Guangai Xue ◽  
Hyun Jae Yu ◽  
Shih Lin Goh ◽  
Anna T. Gres ◽  
Mehmet Hakan Guney ◽  
...  
Keyword(s):  
Nuclear Transport ◽  
Host Factors ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Nuclear Entry ◽  
Critical Determinant ◽  
Subsequent Work ◽  
Biological Assays ◽  
Pore Complexes ◽  
Hiv 1

The movement of viruses and other large macromolecular cargo through nuclear pore complexes (NPCs) is poorly understood. The human immunodeficiency virus type 1 (HIV-1) provides an attractive model to interrogate this process due to the genetic and cell biological assays to score virus nuclear entry in living cells. Although initial studies of HIV-1 infection of nondividing cells focused on karyophilic virion proteins, subsequent work revealed the viral capsid (CA), the chief structural component of the pre-integration complex (PIC), to be a critical determinant in nuclear transport1. In support of this model, HIV-1 interactions with NPCs can be altered through CA mutation2, which makes direct contact with nucleoporins (Nups)3–5. Here we identify Nup35, Nup153, and POM121 to coordinately support HIV-1 nuclear entry. For Nup35 and POM121, this dependence was strongly dependent cyclophilin A (CypA) interaction with CA. Mutation of CA or removal of soluble host factors changed the interaction with the NPC. Collectively, these findings implicate the HIV-1 CA hexameric lattice that encapsulates the viral genome as a macromolecular nuclear transport receptor (NTR) that exploits soluble host factors to modulate NPC requirements during nuclear invasion.

scholarly journals Concepts to Reveal Parvovirus–Nucleus Interactions

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1306
Author(s):  
Salla Mattola ◽  
Satu Hakanen ◽  
Sami Salminen ◽  
Vesa Aho ◽  
Elina Mäntylä ◽  
...  
Keyword(s):  
Life Cycle ◽  
Molecular Interactions ◽  
Structure And Function ◽  
Dna Modification ◽  
Nuclear Entry ◽  
Dna Viruses ◽  
Chromatin Interactions ◽  
Nuclear Stage ◽  
And Function ◽  
Induced Changes

Parvoviruses are small single-stranded (ss) DNA viruses, which replicate in the nucleoplasm and affect both the structure and function of the nucleus. The nuclear stage of the parvovirus life cycle starts at the nuclear entry of incoming capsids and culminates in the successful passage of progeny capsids out of the nucleus. In this review, we will present past, current, and future microscopy and biochemical techniques and demonstrate their potential in revealing the dynamics and molecular interactions in the intranuclear processes of parvovirus infection. In particular, a number of advanced techniques will be presented for the detection of infection-induced changes, such as DNA modification and damage, as well as protein–chromatin interactions.

scholarly journals Impact of DNA methylation on 3D genome structure

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Diana Buitrago ◽  
Mireia Labrador ◽  
Juan Pablo Arcon ◽  
Rafael Lema ◽  
Oscar Flores ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Chromatin Structure ◽  
Chromatin Condensation ◽  
Genome Structure ◽  
Dna Methyltransferases ◽  
Model System ◽  
Structure And Function ◽  
3D Genome ◽  
Cellular Machinery ◽  
And Function

AbstractDetermining the effect of DNA methylation on chromatin structure and function in higher organisms is challenging due to the extreme complexity of epigenetic regulation. We studied a simpler model system, budding yeast, that lacks DNA methylation machinery making it a perfect model system to study the intrinsic role of DNA methylation in chromatin structure and function. We expressed the murine DNA methyltransferases in Saccharomyces cerevisiae and analyzed the correlation between DNA methylation, nucleosome positioning, gene expression and 3D genome organization. Despite lacking the machinery for positioning and reading methylation marks, induced DNA methylation follows a conserved pattern with low methylation levels at the 5’ end of the gene increasing gradually toward the 3’ end, with concentration of methylated DNA in linkers and nucleosome free regions, and with actively expressed genes showing low and high levels of methylation at transcription start and terminating sites respectively, mimicking the patterns seen in mammals. We also see that DNA methylation increases chromatin condensation in peri-centromeric regions, decreases overall DNA flexibility, and favors the heterochromatin state. Taken together, these results demonstrate that methylation intrinsically modulates chromatin structure and function even in the absence of cellular machinery evolved to recognize and process the methylation signal.

scholarly journals RanBP2/Nup358 enhances miRNA activity by sumoylating and stabilizing Argonaute 1

2019 ◽  
Author(s):  
Qingtang Shen ◽  
Yifan E. Wang ◽  
Mathew Truong ◽  
Kohila Mahadevan ◽  
Jing Ze Wu ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Viral Infections ◽  
Nuclear Pore ◽  
Missense Mutations ◽  
Acute Necrotizing Encephalopathy ◽  
Messenger Ribonucleoprotein ◽  
Cytoplasmic Filaments ◽  
Acute Necrotizing ◽  
Main Components ◽  
Ultimate Fate

SUMMARYRanBP2/Nup358 is one of the main components of the cytoplasmic filaments of the nuclear pore complex. It has been speculated that RanBP2, which has an E3 SUMO-ligase domain, may alter the composition of messenger ribonucleoprotein (mRNP) complexes as they emerge from the nuclear pore and thus regulate the ultimate fate of the mRNA in the cytoplasm. Four separate missense mutations in RanBP2 cause Acute Necrotizing Encephalopathy 1 (ANE1), which manifests as a sharp rise in cytokine production after common viral infections such as influenza and parainfluenza. However, how RanBP2 and its ANE1-associated mutations affect cytokine production is not well understood. Here we report that RanBP2 represses the translation of the interleukin-6 (IL6) mRNA, which encodes a cytokine that is aberrantly up-regulated in ANE1. Our data indicates that soon after its production, the IL6 mRNP recruits the RNA-induced silencing complex (RISC) bound to Let7 miRNA. After this mRNP is exported, RanBP2 sumoylates the RISC-component AGO1, thereby stabilizing it and enforcing mRNA silencing. Collectively, these results support a model whereby RanBP2 promotes an mRNP remodelling event that is critical for the miRNA-mediated suppression of clinically relevant mRNAs, such as IL6.

scholarly journals Remote control of microtubule plus-end dynamics and function from the minus-end

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Xiuzhen Chen ◽  
Lukas A Widmer ◽  
Marcel M Stangier ◽  
Michel O Steinmetz ◽  
Jörg Stelling ◽  
...  
Keyword(s):  
Remote Control ◽  
Mother Cell ◽  
Spindle Pole ◽  
Kinesin Motor ◽  
Random Lattice ◽  
Spindle Pole Bodies ◽  
Dividing Cells ◽  
Dynamics And Function ◽  
And Function ◽  
Microtubule Function

In eukaryotes, the organization and function of the microtubule cytoskeleton depend on the allocation of different roles to individual microtubules. For example, many asymmetrically dividing cells differentially specify microtubule behavior at old and new centrosomes. Here we show that yeast spindle pole bodies (SPBs, yeast centrosomes) differentially control the plus-end dynamics and cargoes of their astral microtubules, remotely from the minus-end. The old SPB recruits the kinesin motor protein Kip2, which then translocates to the plus-end of the emanating microtubules, promotes their extension and delivers dynein into the bud. Kip2 recruitment at the SPB depends on Bub2 and Bfa1, and phosphorylation of cytoplasmic Kip2 prevents random lattice binding. Releasing Kip2 of its control by SPBs equalizes its distribution, the length of microtubules and dynein distribution between the mother cell and its bud. These observations reveal that microtubule organizing centers use minus to plus-end directed remote control to individualize microtubule function.

scholarly journals O-GlcNAc modification of nuclear pore complexes accelerates bi-directional transport

2020 ◽  
Author(s):  
Tae Yeon Yoo ◽  
Timothy J Mitchison
Keyword(s):  
Nuclear Import ◽  
Nuclear Transport ◽  
Super Resolution ◽  
Nucleocytoplasmic Transport ◽  
Nuclear Pore ◽  
Permeability Barrier ◽  
Nuclear Pore Complexes ◽  
Facilitated Diffusion ◽  
Import And Export ◽  
Pore Complexes

AbstractMacromolecular transport across the nuclear envelope depends on facilitated diffusion through nuclear pore complexes (NPCs). The interior of NPCs contains a permeability barrier made of phenylalanine-glycine (FG) repeat domains that selectively facilitates the permeation of cargoes bound to nuclear transport receptors (NTRs). FG repeats in NPC are a major site of O-linked N-acetylglucosamine (O-GlcNAc) modification, but the functional role of this modification in nucleocytoplasmic transport is unclear. We developed high-throughput assays based on optogenetic probes to quantify the kinetics of nuclear import and export in living human cells. We found that increasing O-GlcNAc modification of the NPC accelerated NTR-facilitated nucleocytoplasmic transport of proteins in both directions, and decreasing modification slowed transport. Super-resolution imaging revealed strong enrichment of O-GlcNAc at the FG-repeat barrier. O-GlcNAc modification also accelerated passive permeation of a small, inert protein through NPCs. We conclude that O-GlcNAc modification accelerates nucleocytoplasmic transport by enhancing the non-specific permeability the FG-repeat barrier, perhaps by steric inhibition of interactions between FG repeats.SummaryNuclear pore complexes mediate nuclear transport and are highly modified with O-linked N-acetylglucosamine (O-GlcNAc) on FG repeat domains. Using a new quantitative live-cell imaging assay, Yoo and Mitchison demonstrate acceleration of nuclear import and export by O-GlcNAc modification.

scholarly journals Concentration-dependent lamin assembly and its roles in the localization of other nuclear proteins

2014 ◽  
Vol 25 (8) ◽  
pp. 1287-1297 ◽  
Author(s):  
Yuxuan Guo ◽  
Youngjo Kim ◽  
Takeshi Shimi ◽  
Robert D. Goldman ◽  
Yixian Zheng
Keyword(s):  
Nuclear Lamina ◽  
Nuclear Pore ◽  
Lamin A ◽  
Nuclear Pore Complexes ◽  
Developmental Defects ◽  
Protein Levels ◽  
Lamin B1 ◽  
Mouse Cells ◽  
Pore Complexes ◽  
And Function

The nuclear lamina (NL) consists of lamin polymers and proteins that bind to the polymers. Disruption of NL proteins such as lamin and emerin leads to developmental defects and human diseases. However, the expression of multiple lamins, including lamin-A/C, lamin-B1, and lamin-B2, in mammals has made it difficult to study the assembly and function of the NL. Consequently, it has been unclear whether different lamins depend on one another for proper NL assembly and which NL functions are shared by all lamins or are specific to one lamin. Using mouse cells deleted of all or different combinations of lamins, we demonstrate that the assembly of each lamin into the NL depends primarily on the lamin concentration present in the nucleus. When expressed at sufficiently high levels, each lamin alone can assemble into an evenly organized NL, which is in turn sufficient to ensure the even distribution of the nuclear pore complexes. By contrast, only lamin-A can ensure the localization of emerin within the NL. Thus, when investigating the role of the NL in development and disease, it is critical to determine the protein levels of relevant lamins and the intricate shared or specific lamin functions in the tissue of interest.

Identification of four nuclear transport signal-binding proteins that interact with diverse transport signals

1989 ◽  
Vol 9 (7) ◽  
pp. 3028-3036
Author(s):  
L Yamasaki ◽  
P Kanda ◽  
R E Lanford
Keyword(s):  
Binding Proteins ◽  
Nuclear Transport ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Nuclear Pore ◽  
Signal Peptides ◽  
Signal Recognition ◽  
Transport Pathway

The transport of proteins into the nucleus requires not only the presence of a nuclear transport signal on the targeted protein but also the signal recognition proteins and the nuclear pore translocation apparatus. Complicating the search for the signal recognition proteins is the fact that the nuclear transport signals identified share little obvious homology. In this study, synthetic peptides homologous to the nuclear transport signals from the simian virus 40 large T antigen, Xenopus oocyte nucleoplasmin, adenovirus E1A, and Saccharomyces cerevisiae MAT alpha 2 proteins were coupled to a UV-photoactivable cross-linker and iodinated for use in an in vitro cross-linking reaction with cellular lysates. Four proteins, p140, p100, p70, and p55, which specifically interacted with the nuclear transport signal peptides were identified. Unique patterns of reactivity were observed with closely related pairs of nuclear transport signal peptides. Competition experiments with labeled and unlabeled peptides demonstrated that heterologous signals were able to bind the same protein and suggested that diverse signals use a common transport pathway. The subcellular distribution of the four nuclear transport signal-binding proteins suggested that nuclear transport involves both cytoplasmic and nuclear receptors. The four proteins were not bound by wheat germ agglutinin and were not associated tightly with the nuclear pore complex.

Regulation of functional nuclear pore size in fibroblasts

2001 ◽  
Vol 114 (24) ◽  
pp. 4621-4627
Author(s):  
Carl M. Feldherr ◽  
Debra Akin ◽  
Robert J. Cohen
Keyword(s):  
Pore Size ◽  
Transcriptional Activation ◽  
Pore Diameter ◽  
Nuclear Transport ◽  
Control Level ◽  
Proteasome Inhibitors ◽  
Nuclear Pore ◽  
Transport Capacity ◽  
3T3 Cells ◽  
Gold Particles

Protein-NLS-coated gold particles up to approximately 250 Å in diameter are transported through the nuclear pores in normal, proliferating BALB/c 3T3 cells. This size can increase or decrease, depending on cellular activity. It has been suggested that increases in functional pore size are related to a reduction in the amount of available p53. To further test this hypothesis, we investigated the effects of cycloheximide and pifithrin-α, which inhibits p53-dependent transcriptional activation, on nuclear transport. After 3 hours in cycloheximide, there was a significant increase in the size of the gold particles that entered the nucleoplasm. When the incubation period was extended to 6 hours or longer, transport capacity returned to the control level. By using proteasome inhibitors, it was shown that the cycloheximide-dependent increase in functional pore size was due to the inhibition of protein synthesis, consistent with the fact that p53 is a short-lived protein, and requires the activity of at least two different factors. Although cycloheximide increases the functional diameter of the channel available for signal-mediated transport by approximately 60 Å, it had no significant effect on either the import rate of small NLS-containing substrates (FITC-BSA-NLS), or passive diffusion of fluorescent-labeled proteins across the envelope. This suggests that changes in transport capacity were not caused by an increase in overall pore diameter but instead are due to a transient increase in pore size that accompanies signal-mediated transport. Pifithrin-α also caused an increase in functional pore diameter without altering the import rate of FITC-BSA-NLS, providing further support for the view that p53 can initiate changes in nuclear transport capacity.

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