scholarly journals The Role of ND10 Nuclear Bodies in Herpesvirus Infection: A Frenemy for the Virus?

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 239
Author(s):  
Behdokht Jan Fada ◽  
Eleazar Reward ◽  
Haidong Gu
Keyword(s):  
Molecular Mechanisms ◽  
Viral Gene Expression ◽  
Protein Composition ◽  
Nuclear Bodies ◽  
Viral Gene ◽  
Herpesvirus Infection ◽  
Cellular Processes ◽  
Nuclear Domains ◽  
Human Herpesviruses

Nuclear domains 10 (ND10), a.k.a. promyelocytic leukemia nuclear bodies (PML-NBs), are membraneless subnuclear domains that are highly dynamic in their protein composition in response to cellular cues. They are known to be involved in many key cellular processes including DNA damage response, transcription regulation, apoptosis, oncogenesis, and antiviral defenses. The diversity and dynamics of ND10 residents enable them to play seemingly opposite roles under different physiological conditions. Although the molecular mechanisms are not completely clear, the pro- and anti-cancer effects of ND10 have been well established in tumorigenesis. However, in herpesvirus research, until the recently emerged evidence of pro-viral contributions, ND10 nuclear bodies have been generally recognized as part of the intrinsic antiviral defenses that converge to the incoming viral DNA to inhibit the viral gene expression. In this review, we evaluate the newly discovered pro-infection influences of ND10 in various human herpesviruses and analyze their molecular foundation along with the traditional antiviral functions of ND10. We hope to shed light on the explicit role of ND10 in both the lytic and latent cycles of herpesvirus infection, which is imperative to the delineation of herpes pathogenesis and the development of prophylactic/therapeutic treatments for herpetic diseases.

scholarly journals Gamma Interferon Blocks Gammaherpesvirus Reactivation from Latency

2006 ◽  
Vol 80 (1) ◽  
pp. 192-200 ◽  
Author(s):  
Ashley L. Steed ◽  
Erik S. Barton ◽  
Scott A. Tibbetts ◽  
Daniel L. Popkin ◽  
Mary L. Lutzke ◽  
...  
Keyword(s):  
Immune Surveillance ◽  
Viral Gene Expression ◽  
Gamma Interferon ◽  
Viral Gene ◽  
Herpesvirus Infection ◽  
Murine Gammaherpesvirus ◽  
Ifn Γ ◽  
Gammaherpesvirus 68 ◽  
Novel Strategy

ABSTRACT Establishment of latent infection and reactivation from latency are critical aspects of herpesvirus infection and pathogenesis. Interfering with either of these steps in the herpesvirus life cycle may offer a novel strategy for controlling herpesvirus infection and associated disease pathogenesis. Prior studies show that mice deficient in gamma interferon (IFN-γ) or the IFN-γ receptor have elevated numbers of cells reactivating from murine gammaherpesvirus 68 (γHV68) latency, produce infectious virus after the establishment of latency, and develop large-vessel vasculitis. Here, we demonstrate that IFN-γ is a powerful inhibitor of reactivation of γHV68 from latency in tissue culture. In vivo, IFN-γ controls viral gene expression during latency. Importantly, depletion of IFN-γ in latently infected mice results in an increased frequency of cells reactivating virus. This demonstrates that IFN-γ is important for immune surveillance that limits reactivation of γHV68 from latency.

scholarly journals Role of Long Non-Coding RNA Polymorphisms in Cancer Chemotherapeutic Response

2021 ◽  
Vol 11 (6) ◽  
pp. 513
Author(s):  
Zheng Zhang ◽  
Meng Gu ◽  
Zhongze Gu ◽  
Yan-Ru Lou
Keyword(s):  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Cellular Processes ◽  
Dna And Rna ◽  
Chemotherapeutic Response ◽  
Non Coding Rna ◽  
Response To Chemotherapy ◽  
Personalized Oncology ◽  
Long Non Coding Rna

Genetic polymorphisms are defined as the presence of two or more different alleles in the same locus, with a frequency higher than 1% in the population. Since the discovery of long non-coding RNAs (lncRNAs), which refer to a non-coding RNA with a length of more than 200 nucleotides, their biological roles have been increasingly revealed in recent years. They regulate many cellular processes, from pluripotency to cancer. Interestingly, abnormal expression or dysfunction of lncRNAs is closely related to the occurrence of human diseases, including cancer and degenerative neurological diseases. Particularly, their polymorphisms have been found to be associated with altered drug response and/or drug toxicity in cancer treatment. However, molecular mechanisms are not yet fully elucidated, which are expected to be discovered by detailed studies of RNA–protein, RNA–DNA, and RNA–lipid interactions. In conclusion, lncRNAs polymorphisms may become biomarkers for predicting the response to chemotherapy in cancer patients. Here we review and discuss how gene polymorphisms of lncRNAs affect cancer chemotherapeutic response. This knowledge may pave the way to personalized oncology treatments.

scholarly journals Modulation of Endosome Function, Vesicle Trafficking and Autophagy by Human Herpesviruses

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 542
Author(s):  
Eduardo I. Tognarelli ◽  
Antonia Reyes ◽  
Nicolás Corrales ◽  
Leandro J. Carreño ◽  
Susan M. Bueno ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Viral Gene ◽  
Barr Virus ◽  
Cellular Processes ◽  
Antiviral Therapies ◽  
Host Determinants ◽  
Viral Particles ◽  
Life Threatening ◽  
Epstein Barr ◽  
Human Herpesviruses

Human herpesviruses are a ubiquitous family of viruses that infect individuals of all ages and are present at a high prevalence worldwide. Herpesviruses are responsible for a broad spectrum of diseases, ranging from skin and mucosal lesions to blindness and life-threatening encephalitis, and some of them, such as Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein–Barr virus (EBV), are known to be oncogenic. Furthermore, recent studies suggest that some herpesviruses may be associated with developing neurodegenerative diseases. These viruses can establish lifelong infections in the host and remain in a latent state with periodic reactivations. To achieve infection and yield new infectious viral particles, these viruses require and interact with molecular host determinants for supporting their replication and spread. Important sets of cellular factors involved in the lifecycle of herpesviruses are those participating in intracellular membrane trafficking pathways, as well as autophagic-based organelle recycling processes. These cellular processes are required by these viruses for cell entry and exit steps. Here, we review and discuss recent findings related to how herpesviruses exploit vesicular trafficking and autophagy components by using both host and viral gene products to promote the import and export of infectious viral particles from and to the extracellular environment. Understanding how herpesviruses modulate autophagy, endolysosomal and secretory pathways, as well as other prominent trafficking vesicles within the cell, could enable the engineering of novel antiviral therapies to treat these viruses and counteract their negative health effects.

Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

2018 ◽  
Vol 25 (1) ◽  
pp. 5-21 ◽  
Author(s):  
Ylenia Cau ◽  
Daniela Valensin ◽  
Mattia Mori ◽  
Sara Draghi ◽  
Maurizio Botta
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Specific Protein ◽  
Protein Protein Interactions ◽  
Cellular Processes ◽  
Protein Partners ◽  
High Sequence Homology ◽  
Small Molecule Modulators

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

Role of the avian retrovirus mRNA leader in expression: evidence for novel translational control

1986 ◽  
Vol 6 (2) ◽  
pp. 372-379
Author(s):  
R A Katz ◽  
B R Cullen ◽  
R Malavarca ◽  
A M Skalka
Keyword(s):  
Translational Control ◽  
Consensus Sequence ◽  
Viral Gene Expression ◽  
State Level ◽  
Viral Gene ◽  
Translational Initiation ◽  
Efficient Expression ◽  
Expression Characterization ◽  
Expression Evidence

Avian retroviral mRNAs contain a long 5' untranslated leader of approximately 380 nucleotides. The leader includes sequences required for viral replication and three AUG codons which precede the AUG codon used for translational initiation of the gag and env genes. We have used sensitive, quantitative assays of viral gene transcription and translation to analyze the role of this mRNA leader in viral gene expression. By substituting segments from related viruses, we had previously shown that the endogenous avian provirus ev-1 contained a defective leader segment (B. R. Cullen, A. M. Skalka, and G. Ju, Proc. Natl. Acad. Sci. USA 80:2946-2950, 1983). The sequence analysis presented here, followed by comparison with the nondefective ev-2 endogenous provirus segment, identified the critical changes at nucleotides 4 and 7 upstream of the initiator AUG. These differences do not alter the most conserved nucleotides within the consensus sequence which precedes eucaryotic initiation codons, but lie within a nine-nucleotide region that is otherwise highly conserved among avian retrovirus strains. Analysis of a series of deletion mutants indicated that other sequences within the leader are also required for efficient expression. Characterization of the altered transcripts demonstrated that the presence of the defective ev-1 segment or the deletion of a ca. 200-nucleotide leader segment did not affect the steady-state level or splicing efficiency of these mRNAs. Thus, we conclude that the reduced expression of these mRNAs is due to a translational deficiency. These results indicate that specific leader sequences, other than the previously identified consensus nucleotides which precede eucaryotic AUG initiator codons, can influence eucaryotic gene translation.

scholarly journals Genome Size and Structure Determine Efficiency of Postinternalization Steps and Gene Transfer of Capsid-Modified Adenovirus Vectors in a Cell-Type-Specific Manner

2004 ◽  
Vol 78 (18) ◽  
pp. 10009-10022 ◽  
Author(s):  
Dmitry M. Shayakhmetov ◽  
Zong-Yi Li ◽  
Anuj Gaggar ◽  
Helen Gharwan ◽  
Vladimir Ternovoi ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Genome Size ◽  
First Generation ◽  
Viral Gene Expression ◽  
Protein Composition ◽  
Cell Types ◽  
Helper Virus ◽  
Viral Gene ◽  
Viral Genes ◽  
Size And Structure

ABSTRACT Adenovirus serotype 5 (Ad5) vectors containing Ad B-group fibers have become increasingly popular as gene transfer vectors because they efficiently transduce human cell types that are relatively refractory to Ad5 infection. So far, most B-group fiber-containing vectors have been first-generation vectors, deleted of E1 and/or E3 genes. Transduction with these vectors, however, results in viral gene expression and is associated with cytotoxicity and immune responses against transduced cells. To circumvent these problems, we developed fiber-chimeric Ad vectors devoid of all viral genes that were produced either by the homologous recombination of first-generation vectors or by using the Cre/lox-based helper virus system. In this study we compared early steps of infection between first-generation (35-kb genome) and Ad vectors devoid of all viral genes with genome sizes of 28 kb and 12.6 kb. All vectors possessed an Ad35-derived fiber knob domain, which uses CD46 as a primary attachment receptor. Using immortalized human hematopoietic cell lines and primary human CD34-positive hematopoietic cells, we found that the Ad genome size did not affect the efficiency of virus attachment to and internalization into cells. Furthermore, independently of the genome length and structure, all vectors migrated to the nucleus through late endosomal and lysosomal cellular compartments. However, the vector containing the short 12.6-kb genome was unable to efficiently escape from endosomes and deliver its DNA into the nucleus. Moreover, compared to other vectors, these Ad particles were less stable and had an abnormal capsid protein composition, including a lack of capsid-stabilizing protein IX. Our data indicate that the size and structure of the packaged viral genomes can affect the integrity of Ad particles, which in turn results in lower infectivity of Ad vectors.

Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease

2011 ◽  
Vol 439 (3) ◽  
pp. 349-378 ◽  
Author(s):  
Anthony J. Morgan ◽  
Frances M. Platt ◽  
Emyr Lloyd-Evans ◽  
Antony Galione
Keyword(s):  
Molecular Mechanisms ◽  
Cellular Processes ◽  
Late Endosomes ◽  
Wide Range ◽  
Health And Disease ◽  
Lysosome Related Organelles ◽  
Cellular Compartments ◽  
Endosomal Vesicles ◽  
Intracellular Targets

Endosomes, lysosomes and lysosome-related organelles are emerging as important Ca2+ storage cellular compartments with a central role in intracellular Ca2+ signalling. Endocytosis at the plasma membrane forms endosomal vesicles which mature to late endosomes and culminate in lysosomal biogenesis. During this process, acquisition of different ion channels and transporters progressively changes the endolysosomal luminal ionic environment (e.g. pH and Ca2+) to regulate enzyme activities, membrane fusion/fission and organellar ion fluxes, and defects in these can result in disease. In the present review we focus on the physiology of the inter-related transport mechanisms of Ca2+ and H+ across endolysosomal membranes. In particular, we discuss the role of the Ca2+-mobilizing messenger NAADP (nicotinic acid adenine dinucleotide phosphate) as a major regulator of Ca2+ release from endolysosomes, and the recent discovery of an endolysosomal channel family, the TPCs (two-pore channels), as its principal intracellular targets. Recent molecular studies of endolysosomal Ca2+ physiology and its regulation by NAADP-gated TPCs are providing exciting new insights into the mechanisms of Ca2+-signal initiation that control a wide range of cellular processes and play a role in disease. These developments underscore a new central role for the endolysosomal system in cellular Ca2+ regulation and signalling.

scholarly journals Mechanisms of Proteinuria in HIV

2021 ◽  
Vol 8 ◽  
Author(s):  
Gentzon Hall ◽  
Christina M. Wyatt
Keyword(s):  
Kidney Disease ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Glomerular Diseases ◽  
Animal Models Of Disease ◽  
Filtration Barrier ◽  
Models Of Disease ◽  
Susceptible Populations

Proteinuria is common in the setting of HIV infection, and may reflect comorbid kidney disease, treatment-related nephrotoxicity, and HIV-related glomerular diseases. The mechanisms of podocyte and tubulointerstial injury in HIV-associated nephropathy (HIVAN) have been the subject of intense investigation over the past four decades. The pathologic contributions of viral gene expression, dysregulated innate immune signaling, and ancestry-driven genetic risk modifiers have been explored in sophisticated cellular and whole animal models of disease. These studies provide evidence that injury-induced podocyte dedifferentiation, hyperplasia, cytoskeletal dysregulation, and apoptosis may cause the loss of glomerular filtration barrier integrity and slit diaphragm performance that facilitates proteinuria and tuft collapse in HIVAN. Although the incidence of HIVAN has declined with the introduction of antiretroviral therapy, the collapsing FSGS lesion has been observed in the context of other viral infections and chronic autoimmune disorders, and with the use of interferon-based therapies in genetically susceptible populations. This highlights the fact that the lesion is not specific to HIVAN and that the role of the immune system in aggravating podocyte injury warrants further exploration. This review will summarize our progress in characterizing the molecular mechanisms of podocyte dysfunction in HIVAN and other forms of HIV-associated kidney disease.

scholarly journals When the chains do not break: the role of USP10 in physiology and pathology

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Udayan Bhattacharya ◽  
Fiifi Neizer-Ashun ◽  
Priyabrata Mukherjee ◽  
Resham Bhattacharya
Keyword(s):  
Complex Formation ◽  
Molecular Mechanisms ◽  
Protein Homeostasis ◽  
Post Translational Modification ◽  
Intracellular Protein ◽  
Lysosomal Degradation ◽  
Life Activity ◽  
Cellular Processes ◽  
Pathological Conditions

AbstractDeubiquitination is now understood to be as important as its partner ubiquitination for the maintenance of protein half-life, activity, and localization under both normal and pathological conditions. The enzymes that remove ubiquitin from target proteins are called deubiquitinases (DUBs) and they regulate a plethora of cellular processes. DUBs are essential enzymes that maintain intracellular protein homeostasis by recycling ubiquitin. Ubiquitination is a post-translational modification where ubiquitin molecules are added to proteins thus influencing activation, localization, and complex formation. Ubiquitin also acts as a tag for protein degradation, especially by proteasomal or lysosomal degradation systems. With ~100 members, DUBs are a large enzyme family; the ubiquitin-specific peptidases (USPs) being the largest group. USP10, an important member of this family, has enormous significance in diverse cellular processes and many human diseases. In this review, we discuss recent studies that define the roles of USP10 in maintaining cellular function, its involvement in human pathologies, and the molecular mechanisms underlying its association with cancer and neurodegenerative diseases. We also discuss efforts to modulate USPs as therapy in these diseases.

Regulation of hemidesmosome dynamics and cell signaling by integrin α6β4

2021 ◽  
Vol 134 (18) ◽  
Author(s):  
Lisa te Molder ◽  
Jose M. de Pereda ◽  
Arnoud Sonnenberg
Keyword(s):  
Signal Transduction ◽  
Extracellular Matrix ◽  
Cell Adhesion ◽  
Epithelial Cells ◽  
Basement Membrane ◽  
Molecular Mechanisms ◽  
Vital Role ◽  
Cellular Processes ◽  
Integrin Α6β4

ABSTRACT Hemidesmosomes (HDs) are specialized multiprotein complexes that connect the keratin cytoskeleton of epithelial cells to the extracellular matrix (ECM). In the skin, these complexes provide stable adhesion of basal keratinocytes to the underlying basement membrane. Integrin α6β4 is a receptor for laminins and plays a vital role in mediating cell adhesion by initiating the assembly of HDs. In addition, α6β4 has been implicated in signal transduction events that regulate diverse cellular processes, including proliferation and survival. In this Review, we detail the role of α6β4 in HD assembly and beyond, and we discuss the molecular mechanisms that regulate its function.

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