scholarly journals The Alphaviral Capsid Protein Inhibits IRAK1-Dependent TLR Signaling

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 377
Author(s):  
V. Douglas Landers ◽  
Daniel W. Wilkey ◽  
Michael L. Merchant ◽  
Thomas C. Mitchell ◽  
Kevin J. Sokoloski
Keyword(s):  
Capsid Protein ◽  
Protein Interactions ◽  
Viral Gene Expression ◽  
Encephalitis Virus ◽  
Model Systems ◽  
Viral Gene ◽  
Protein Protein Interactions ◽  
Equine Encephalitis Virus ◽  
Host Pathogen ◽  
The Impact

Alphaviruses are arthropod-borne RNA viruses which can cause either mild to severe febrile arthritis which may persist for months, or encephalitis which can lead to death or lifelong cognitive impairments. The non-assembly molecular role(s), functions, and protein–protein interactions of the alphavirus capsid proteins have been largely overlooked. Here we detail the use of a BioID2 biotin ligase system to identify the protein–protein interactions of the Sindbis virus capsid protein. These efforts led to the discovery of a series of novel host–pathogen interactions, including the identification of an interaction between the alphaviral capsid protein and the host IRAK1 protein. Importantly, this capsid–IRAK1 interaction is conserved across multiple alphavirus species, including arthritogenic alphaviruses SINV, Ross River virus, and Chikungunya virus; and encephalitic alphaviruses Eastern Equine Encephalitis virus, and Venezuelan Equine Encephalitis virus. The impact of the capsid–IRAK1 interaction was evaluated using a robust set of cellular model systems, leading to the realization that the alphaviral capsid protein specifically inhibits IRAK1-dependent signaling. This inhibition represents a means by which alphaviruses may evade innate immune detection and activation prior to viral gene expression. Altogether, these data identify novel capsid protein–protein interactions, establish the capsid–IRAK1 interaction as a common alphavirus host–pathogen interface, and delineate the molecular consequences of the capsid–IRAK1 interaction on IRAK1-dependent signaling.

scholarly journals The Autoregulatory and Transactivating Functions of the Human Cytomegalovirus IE86 Protein Use Independent Mechanisms for Promoter Binding

2007 ◽  
Vol 81 (11) ◽  
pp. 5807-5818 ◽  
Author(s):  
Dustin T. Petrik ◽  
Kimberly P. Schmitt ◽  
Mark F. Stinski
Keyword(s):  
Human Cytomegalovirus ◽  
Protein Interactions ◽  
Chromatin Immunoprecipitation ◽  
Viral Gene Expression ◽  
Artificial Chromosome ◽  
Viral Gene ◽  
Chip Assay ◽  
Protein Protein Interactions ◽  
Multiple Sequence ◽  
Viral Genes

ABSTRACT The functions of the human cytomegalovirus (HCMV) IE86 protein are paradoxical, as it can both activate and repress viral gene expression through interaction with the promoter region. Although the mechanism for these functions is not clearly defined, it appears that a combination of direct DNA binding and protein-protein interactions is involved. Multiple sequence alignment of several HCMV IE86 homologs reveals that the amino acids 534LPIYE538 are conserved between all primate and nonprimate CMVs. In the context of a bacterial artificial chromosome (BAC), mutation of both P535 and Y537 to alanines (P535A/Y537A) results in a nonviable BAC. The defective HCMV BAC does not undergo DNA replication, although the P535A/Y537A mutant IE86 protein appears to be stably expressed. The P535A/Y537A mutant IE86 protein is able to negatively autoregulate transcription from the major immediate-early (MIE) promoter and was recruited to the MIE promoter in a chromatin immunoprecipitation (ChIP) assay. However, the P535A/Y537A mutant IE86 protein was unable to transactivate early viral genes and was not recruited to the early viral UL4 and UL112 promoters in a ChIP assay. From these data, we conclude that the transactivation and repressive functions of the HCMV IE86 protein can be separated and must occur through independent mechanisms.

scholarly journals Divide et Impera: An In Silico Screening Targeting HCMV ppUL44 Processivity Factor Homodimerization Identifies Small Molecules Inhibiting Viral Replication

2020 ◽  
Author(s):  
Hanieh Ghassabian ◽  
Federico Falchi ◽  
Martina Timmoneri ◽  
Beatrice Mercorelli ◽  
Arianna Loregian ◽  
...  
Keyword(s):  
Small Molecules ◽  
Dna Polymerase ◽  
Protein Interactions ◽  
In Silico ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Protein Protein Interactions ◽  
In Silico Screening ◽  
Infected Cells ◽  
Processivity Factor

Human cytomegalovirus (HCMV) is a leading cause of severe diseases in immunocompromised individuals, including AIDS and transplanted patients, and in congenitally infected newborns. The utility of available drugs is limited by poor bioavailability, toxicity, and emergence of resistant strains. Therefore, it is crucial to identify new targets of therapeutic intervention. Among the latter, viral protein-protein interactions are becoming increasingly attractive. Since dimerization of HCMV DNA polymerase processivity factor ppUL44 plays an essential role in the viral life cycle being required for oriLyt-dependent DNA replication, we performed an in silico screening and selected 18 small molecules (SMs) potentially interfering with ppUL44 homodimerization. Antiviral assays using recombinant HCMV TB40-UL83-YFP in the presence of the selected SMs led to the identification of four active compounds. The most active one, B3, also efficiently inhibited AD169 in plaque reduction assays and impaired replication of an AD169-GFP reporter virus and its ganciclovir-resistant counterpart to a similar extent. As assessed by Western blotting experiments, treatment of infected cells with B3 specifically reduced viral gene expression starting from 48 h post infection, consistent with activity on viral DNA synthesis. Therefore, inhibition of ppUL44 dimerization could represent a new class of HCMV inhibitors, complementary to those targeting the DNA polymerase catalytic subunit or the viral terminase complex.

scholarly journals Divide et impera: An In Silico Screening Targeting HCMV ppUL44 Processivity Factor Homodimerization Identifies Small Molecules Inhibiting Viral Replication

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 941
Author(s):  
Hanieh Ghassabian ◽  
Federico Falchi ◽  
Martina Timmoneri ◽  
Beatrice Mercorelli ◽  
Arianna Loregian ◽  
...  
Keyword(s):  
Small Molecules ◽  
Dna Polymerase ◽  
Protein Interactions ◽  
Post Infection ◽  
In Silico ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Protein Protein Interactions ◽  
In Silico Screening ◽  
Processivity Factor

Human cytomegalovirus (HCMV) is a leading cause of severe diseases in immunocompromised individuals, including AIDS patients and transplant recipients, and in congenitally infected newborns. The utility of available drugs is limited by poor bioavailability, toxicity, and emergence of resistant strains. Therefore, it is crucial to identify new targets for therapeutic intervention. Among the latter, viral protein–protein interactions are becoming increasingly attractive. Since dimerization of HCMV DNA polymerase processivity factor ppUL44 plays an essential role in the viral life cycle, being required for oriLyt-dependent DNA replication, it can be considered a potential therapeutic target. We therefore performed an in silico screening and selected 18 small molecules (SMs) potentially interfering with ppUL44 homodimerization. Antiviral assays using recombinant HCMV TB4-UL83-YFP in the presence of the selected SMs led to the identification of four active compounds. The most active one, B3, also efficiently inhibited HCMV AD169 strain in plaque reduction assays and impaired replication of an AD169-GFP reporter virus and its ganciclovir-resistant counterpart to a similar extent. As assessed by Western blotting experiments, B3 specifically reduced viral gene expression starting from 48 h post infection, consistent with the inhibition of viral DNA synthesis measured by qPCR starting from 72 h post infection. Therefore, our data suggest that inhibition of ppUL44 dimerization could represent a new class of HCMV inhibitors, complementary to those targeting the DNA polymerase catalytic subunit or the viral terminase complex.

scholarly journals The Protein Interactome of Glycolysis in Escherichia coli

Proteomes ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 16
Author(s):  
Shomeek Chowdhury ◽  
Stephen Hepper ◽  
Mudassir K. Lodi ◽  
Milton H. Saier ◽  
Peter Uetz
Keyword(s):  
Escherichia Coli ◽  
Protein Interactions ◽  
Allosteric Regulation ◽  
Glycolytic Enzymes ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Interacting Protein ◽  
E Coli ◽  
Protein Interactome ◽  
The Impact

Glycolysis is regulated by numerous mechanisms including allosteric regulation, post-translational modification or protein-protein interactions (PPI). While glycolytic enzymes have been found to interact with hundreds of proteins, the impact of only some of these PPIs on glycolysis is well understood. Here we investigate which of these interactions may affect glycolysis in E. coli and possibly across numerous other bacteria, based on the stoichiometry of interacting protein pairs (from proteomic studies) and their conservation across bacteria. We present a list of 339 protein-protein interactions involving glycolytic enzymes but predict that ~70% of glycolytic interactors are not present in adequate amounts to have a significant impact on glycolysis. Finally, we identify a conserved but uncharacterized subset of interactions that are likely to affect glycolysis and deserve further study.

scholarly journals TRIM22. A Multitasking Antiviral Factor

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1864
Author(s):  
Isabel Pagani ◽  
Guido Poli ◽  
Elisa Vicenzi
Keyword(s):  
Protein Interactions ◽  
Influenza A ◽  
Direct Interaction ◽  
Type I Interferons ◽  
Viral Gene ◽  
Target Cells ◽  
Type I ◽  
Protein Protein Interactions ◽  
Viral Genomes ◽  
Dna And Rna

Viral invasion of target cells triggers an immediate intracellular host defense system aimed at preventing further propagation of the virus. Viral genomes or early products of viral replication are sensed by a number of pattern recognition receptors, leading to the synthesis and production of type I interferons (IFNs) that, in turn, activate a cascade of IFN-stimulated genes (ISGs) with antiviral functions. Among these, several members of the tripartite motif (TRIM) family are antiviral executors. This article will focus, in particular, on TRIM22 as an example of a multitarget antiviral member of the TRIM family. The antiviral activities of TRIM22 against different DNA and RNA viruses, particularly human immunodeficiency virus type 1 (HIV-1) and influenza A virus (IAV), will be discussed. TRIM22 restriction of virus replication can involve either direct interaction of TRIM22 E3 ubiquitin ligase activity with viral proteins, or indirect protein–protein interactions resulting in control of viral gene transcription, but also epigenetic effects exerted at the chromatin level.

scholarly journals Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 283
Author(s):  
Michael D. Barrera ◽  
Victoria Callahan ◽  
Ivan Akhrymuk ◽  
Nishank Bhalla ◽  
Weidong Zhou ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Trafficking ◽  
Viral Protein ◽  
Sindbis Virus ◽  
Encephalitis Virus ◽  
Host Proteins ◽  
Atp Production ◽  
Equine Encephalitis Virus ◽  
E2 Glycoprotein ◽  
Late Stages

Alphaviruses are a genus of the Togaviridae family and are widely distributed across the globe. Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV), cause encephalitis and neurological sequelae while chikungunya virus (CHIKV) and Sindbis virus (SINV) cause arthralgia. There are currently no approved therapeutics or vaccines available for alphaviruses. In order to identify novel therapeutics, a V5 epitope tag was inserted into the N-terminus of the VEEV E2 glycoprotein and used to identify host-viral protein interactions. Host proteins involved in protein folding, metabolism/ATP production, translation, cytoskeleton, complement, vesicle transport and ubiquitination were identified as VEEV E2 interactors. Multiple inhibitors targeting these host proteins were tested to determine their effect on VEEV replication. The compound HA15, a GRP78 inhibitor, was found to be an effective inhibitor of VEEV, EEEV, CHIKV, and SINV. VEEV E2 interaction with GRP78 was confirmed through coimmunoprecipitation and colocalization experiments. Mechanism of action studies found that HA15 does not affect viral RNA replication but instead affects late stages of the viral life cycle, which is consistent with GRP78 promoting viral assembly or viral protein trafficking.

Swim-exercised mice show a decreased level of protein O-GlcNAcylation and expression of O-GlcNAc transferase in heart

2011 ◽  
Vol 111 (1) ◽  
pp. 157-162 ◽  
Author(s):  
Darrell D. Belke
Keyword(s):  
Protein Interactions ◽  
Contractile Function ◽  
Cell Physiology ◽  
Protein Protein Interactions ◽  
Training Exercise ◽  
General Protein ◽  
Exercise Induced ◽  
Glcnac Transferase ◽  
The Impact ◽  
Physiological Hypertrophy

Swim-training exercise in mice leads to cardiac remodeling associated with an improvement in contractile function. Protein O-linked N-acetylglucosamine ( O-GlcNAcylation) is a posttranslational modification of serine and threonine residues capable of altering protein-protein interactions affecting gene transcription, cell signaling pathways, and general cell physiology. Increased levels of protein O-GlcNAcylation in the heart have been associated with pathological conditions such as diabetes, ischemia, and hypertrophic heart failure. In contrast, the impact of physiological exercise on protein O-GlcNAcylation in the heart is currently unknown. Swim-training exercise in mice was associated with the development of a physiological hypertrophy characterized by an improvement in contractile function relative to sedentary mice. General protein O-GlcNAcylation was significantly decreased in swim-exercised mice. This effect was mirrored in the level of O-GlcNAcylation of individual proteins such as SP1. The decrease in protein O-GlcNAcylation was associated with a decrease in the expression of O-GlcNAc transferase (OGT) and glutamine-fructose amidotransferase (GFAT) 2 mRNA. O-GlcNAcase (OGA) activity was actually lower in swim-trained than sedentary hearts, suggesting that it did not contribute to the decreased protein O-GlcNAcylation. Thus it appears that exercise-induced physiological hypertrophy is associated with a decrease in protein O-GlcNAcylation, which could potentially contribute to changes in gene expression and other physiological changes associated with exercise.

scholarly journals Bacteria Use Structural Imperfect Mimicry To Hijack The Host Interactome

2020 ◽  
Author(s):  
Natalia Sanchez de Groot ◽  
Marc Torrent Burgas
Keyword(s):  
Protein Interactions ◽  
Rational Design ◽  
Protein Protein Interactions ◽  
Host Proteins ◽  
Eukaryotic Proteins ◽  
Host Pathogen ◽  
Imperfect Mimicry ◽  
The Way

ABSTRACTBacteria use protein-protein interactions to infect their hosts and hijack fundamental pathways, which ensures their survival and proliferation. Hence, the infectious capacity of the pathogen is closely related to its ability to interact with host proteins. Here, we show that hubs in the host-pathogen interactome are isolated in the pathogen network by adapting the geometry of the interacting interfaces. An imperfect mimicry of the eukaryotic interfaces allows pathogen proteins to actively bind to the host’s target while preventing deleterious effects on the pathogen interactome. Understanding how bacteria recognize eukaryotic proteins may pave the way for the rational design of new antibiotic molecules.

scholarly journals An Integrative Computational Approach for the Prediction of Human-Plasmodium Protein-Protein Interactions

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Kais Ghedira ◽  
Yosr Hamdi ◽  
Abir El Béji ◽  
Houcemeddine Othman
Keyword(s):  
Protein Interactions ◽  
Computational Approach ◽  
Protein Protein Interactions ◽  
Human Red Blood Cells ◽  
Pharmacological Targets ◽  
Host Pathogen ◽  
Human Proteins ◽  
Life Threatening ◽  
Similarity Method ◽  
Human Plasmodium

Host-pathogen molecular cross-talks are critical in determining the pathophysiology of a specific infection. Most of these cross-talks are mediated via protein-protein interactions between the host and the pathogen (HP-PPI). Thus, it is essential to know how some pathogens interact with their hosts to understand the mechanism of infections. Malaria is a life-threatening disease caused by an obligate intracellular parasite belonging to the Plasmodium genus, of which P. falciparum is the most prevalent. Several previous studies predicted human-plasmodium protein-protein interactions using computational methods have demonstrated their utility, accuracy, and efficiency to identify the interacting partners and therefore complementing experimental efforts to characterize host-pathogen interaction networks. To predict potential putative HP-PPIs, we use an integrative computational approach based on the combination of multiple OMICS-based methods including human red blood cells (RBC) and Plasmodium falciparum 3D7 strain expressed proteins, domain-domain based PPI, similarity of gene ontology terms, structure similarity method homology identification, and machine learning prediction. Our results reported a set of 716 protein interactions involving 302 human proteins and 130 Plasmodium proteins. This work provides a list of potential human-Plasmodium interacting proteins. These findings will contribute to better understand the mechanisms underlying the molecular determinism of malaria disease and potentially to identify candidate pharmacological targets.

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