scholarly journals ADAR1 limits stress granule formation through both translation-dependent and translation-independent mechanisms

2021 ◽  
Author(s):  
Giulia A. Corbet ◽  
James M. Burke ◽  
Roy Parker
Keyword(s):  
Immune Response ◽  
Stress Response ◽  
Protein Interactions ◽  
Binding Activity ◽  
Innate Immune ◽  
Protein Protein Interactions ◽  
Granule Formation ◽  
Translation Inhibition ◽  
Translation Repression ◽  
Dsrna Binding

Stress granules (SGs) are cytoplasmic assemblies of RNA and protein that form when translation is repressed during the integrated stress response (ISR). SGs assemble from the combination of RNA-RNA, RNA-protein, and protein-protein interactions between mRNPs. The protein Adenosine deaminase acting on RNA 1 (ADAR1) recognizes and modifies dsRNAs within cells to prevent an aberrant innate immune response. ADAR1 localizes to SGs, and since RNA-RNA interactions contribute to SG assembly and dsRNA induces SGs, we examined how ADAR1 affects SG formation. First, we demonstrate that ADAR1 depletion triggers SGs by allowing endogenous dsRNA to activate the ISR through PKR activation and translation repression. However, we also show that ADAR1 limits SG formation independently of translation inhibition. ADAR1 repression of SGs is independent of deaminase activity, but dependent on dsRNA-binding activity, suggesting a model where ADAR1 binding limits RNA-RNA and/or RNA-protein interactions necessary for recruitment to SGs. Given that ADAR1 expression is induced during viral infection, these findings have implications for ADAR1's role in the antiviral response.

scholarly journals The Viral Macrodomain Counters Host Antiviral ADP-Ribosylation

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 384 ◽  
Author(s):  
Yousef M. O. Alhammad ◽  
Anthony R. Fehr
Keyword(s):  
Immune Responses ◽  
Protein Interactions ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Protein Protein Interactions ◽  
Granule Formation ◽  
Inflammatory Cytokine Production ◽  
Adp Ribosylation ◽  
Antiviral Responses ◽  
Host Defense Response

Macrodomains, enzymes that remove ADP-ribose from proteins, are encoded by several families of RNA viruses and have recently been shown to counter innate immune responses to virus infection. ADP-ribose is covalently attached to target proteins by poly-ADP-ribose polymerases (PARPs), using nicotinamide adenine dinucleotide (NAD+) as a substrate. This modification can have a wide variety of effects on proteins including alteration of enzyme activity, protein–protein interactions, and protein stability. Several PARPs are induced by interferon (IFN) and are known to have antiviral properties, implicating ADP-ribosylation in the host defense response and suggesting that viral macrodomains may counter this response. Recent studies have demonstrated that viral macrodomains do counter the innate immune response by interfering with PARP-mediated antiviral defenses, stress granule formation, and pro-inflammatory cytokine production. Here, we will describe the known functions of the viral macrodomains and review recent literature demonstrating their roles in countering PARP-mediated antiviral responses.

scholarly journals Crystal structure and functional implication of bacterial STING

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Tzu-Ping Ko ◽  
Yu-Chuan Wang ◽  
Chia-Shin Yang ◽  
Mei-Hui Hou ◽  
Chao-Jung Chen ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Driving Force ◽  
Binding Mode ◽  
Innate Immune ◽  
Ligand Specificity ◽  
Protein Protein Interactions ◽  
Recognition Mechanism ◽  
Cyclic Dinucleotides ◽  
Phage Propagation ◽  
Complex Crystal

AbstractMammalian innate immune sensor STING (STimulator of INterferon Gene) was recently found to originate from bacteria. During phage infection, bacterial STING sense c-di-GMP generated by the CD-NTase (cGAS/DncV-like nucleotidyltransferase) encoded in the same operon and signal suicide commitment as a defense strategy that restricts phage propagation. However, the precise binding mode of c-di-GMP to bacterial STING and the specific recognition mechanism are still elusive. Here, we determine two complex crystal structures of bacterial STING/c-di-GMP, which provide a clear picture of how c-di-GMP is distinguished from other cyclic dinucleotides. The protein-protein interactions further reveal the driving force behind filament formation of bacterial STING. Finally, we group the bacterial STING into two classes based on the conserved motif in β-strand lid, which dictate their ligand specificity and oligomerization mechanism, and propose an evolution-based model that describes the transition from c-di-GMP-dependent signaling in bacteria to 2’3’-cGAMP-dependent signaling in eukaryotes.

In silico specificity determination of neoantigen-reactive T-lymphocytes

2021 ◽  
Vol 67 (3) ◽  
pp. 251-258
Author(s):  
A.E. Kniga ◽  
I.V. Polyakov ◽  
A.V. Nemukhin
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Molecular Docking ◽  
Protein Interactions ◽  
Structural Features ◽  
Immune Recognition ◽  
Protein Protein Interactions ◽  
Binary Classifiers

Effective personalized immunotherapies of the future will need to capture not only the peculiarities of the patient’s tumor but also of his immune response to it. In this study, using results of in vitro high-throughput specificity assays, and combining comparative models of pMHCs and TCRs using molecular docking, we have constructed all-atom models for the putative complexes of all their possible pairwise TCR-pMHC combinations. For the models obtained we have calculated a dataset of physics-based scores and have trained binary classifiers that perform better compared to their solely sequence-based counterparts. These structure-based classifiers pinpoint the most prominent energetic terms and structural features characterizing the type of protein-protein interactions that underlies the immune recognition of tumors by T cells.

scholarly journals LRRpredictor—A New LRR Motif Detection Method for Irregular Motifs of Plant NLR Proteins Using an Ensemble of Classifiers

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 286 ◽  
Author(s):  
Eliza C. Martin ◽  
Octavina C. A. Sukarta ◽  
Laurentiu Spiridon ◽  
Laurentiu G. Grigore ◽  
Vlad Constantinescu ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Structural Data ◽  
Innate Immune ◽  
Protein Protein Interactions ◽  
Ensemble Of Classifiers ◽  
Immune Receptor ◽  
Motif Detection ◽  
Protein Architecture ◽  
Recognition Specificity ◽  
Leucine Rich Repeats

Leucine-rich-repeats (LRRs) belong to an archaic procaryal protein architecture that is widely involved in protein–protein interactions. In eukaryotes, LRR domains developed into key recognition modules in many innate immune receptor classes. Due to the high sequence variability imposed by recognition specificity, precise repeat delineation is often difficult especially in plant NOD-like Receptors (NLRs) notorious for showing far larger irregularities. To address this problem, we introduce here LRRpredictor, a method based on an ensemble of estimators designed to better identify LRR motifs in general but particularly adapted for handling more irregular LRR environments, thus allowing to compensate for the scarcity of structural data on NLR proteins. The extrapolation capacity tested on a set of annotated LRR domains from six immune receptor classes shows the ability of LRRpredictor to recover all previously defined specific motif consensuses and to extend the LRR motif coverage over annotated LRR domains. This analysis confirms the increased variability of LRR motifs in plant and vertebrate NLRs when compared to extracellular receptors, consistent with previous studies. Hence, LRRpredictor is able to provide novel insights into the diversification of LRR domains and a robust support for structure-informed analyses of LRRs in immune receptor functioning.

scholarly journals In utero heat stress alters the postnatal innate immune response of pigs

2020 ◽  
Vol 98 (12) ◽  
Author(s):  
Jay S Johnson ◽  
Jacob M Maskal ◽  
Alan W Duttlinger ◽  
Kouassi R Kpodo ◽  
Betty R McConn ◽  
...  
Keyword(s):  
Immune Response ◽  
Heat Stress ◽  
Stress Response ◽  
Body Temperature ◽  
Innate Immune Response ◽  
In Utero ◽  
Innate Immune ◽  
Postnatal Life ◽  
Lps Challenge ◽  
Cell Counts

Abstract The effects of in utero heat stress (IUHS) range from decreased growth performance to altered behavior, but the long-term impact of IUHS on postnatal innate immune function in pigs is unknown. Therefore, the study objective was to determine the effects of early gestation IUHS on the immune, metabolic, and stress response of pigs subjected to an 8 hr lipopolysaccharide (LPS) challenge during postnatal life. Twenty-four pregnant gilts were exposed to thermoneutral (TN; n = 12; 17.5 ± 2.1 °C) or heat stress (HS; n = 12; cyclic 26 to 36 °C) conditions from days 6 to 59 of gestation, and then TN conditions (20.9 ± 2.3 °C) from day 60 of gestation to farrowing. At 12 wk of age, 16 IUHS and 16 in utero thermoneutral (IUTN) pigs were selected, balanced by sex and given an intravenous injection of LPS (2 µg/kg BW mixed with sterile saline [SAL] and injected at 2 µL/kg BW) or SAL (2 µL/kg BW). Body temperature was monitored every 30 min, and blood was obtained at 0, 1, 2, 3, 4, 6, and 8 hr following the LPS challenge. Blood samples were analyzed for glucose, insulin, non-esterified fatty acids (NEFA), cortisol, and cytokine concentrations. In addition, white blood cell counts were determined at 0 and 4 hr. Hour 0 data were used as covariates. Body temperature was increased (P < 0.01) in LPS (40.88 ± 0.08 °C) vs. SAL (39.83 ± 0.08 °C) pigs. Eosinophils tended to be decreased overall (P = 0.09; 43.9%) in IUHS vs. IUTN pigs. Glucose concentrations were reduced overall (P = 0.05; 5.9%) in IUHS vs. IUTN pigs. The NEFA concentrations tended to be greater (P = 0.07; 143.4%) in IUHS-LPS pigs compared with all other treatments, and IUTN-LPS pigs tended to have greater (127.4%) circulating NEFA concentrations compared with IUTN-SAL and IUHS-SAL pigs. Cortisol was increased (P = 0.04) in IUHS-LPS compared with IUTN-LPS pigs at 3 hr (21.5%) and 4 hr (64.3%). At 1 hr, tumor necrosis factor α was increased (P = 0.01; 115.1%) in IUHS-LPS compared with IUTN-LPS pigs. Overall, interleukin-1β (IL-1β) and interleukin-6 (IL-6) were greater (P < 0.04; 281.3% and 297.8%, respectively) in IUHS-LPS pigs compared with all other treatments, and IUTN-LPS pigs had increased IL-1β and IL-6 concentrations compared with IUTN-SAL and IUHS-SAL pigs. In summary, IUHS altered the postnatal cytokine, metabolic, and physiological stress response of pigs during postnatal life, which may have negative implications toward the innate immune response of IUHS pigs to pathogens.

scholarly journals Vaccinia Virus Subverts a Mitochondrial Antiviral Signaling Protein-Dependent Innate Immune Response in Keratinocytes through Its Double-Stranded RNA Binding Protein, E3

2008 ◽  
Vol 82 (21) ◽  
pp. 10735-10746 ◽  
Author(s):  
Liang Deng ◽  
Peihong Dai ◽  
Tanvi Parikh ◽  
Hua Cao ◽  
Vijay Bhoj ◽  
...  
Keyword(s):  
Immune Response ◽  
Vaccinia Virus ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Antiviral Signaling ◽  
Double Stranded Rna ◽  
Signaling Protein ◽  
Dsrna Binding ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein

ABSTRACT Skin keratinocytes provide a first line of defense against invading microorganisms in two ways: (i) by acting as a physical barrier to pathogen entry and (ii) by initiating a vigorous innate immune response upon sensing danger signals. How keratinocytes detect virus infections and generate antiviral immune responses is not well understood. Orthopoxviruses are dermatotropic DNA viruses that cause lethal disease in humans. Virulence in animal models depends on the virus-encoded bifunctional Z-DNA/double-stranded RNA (dsRNA)-binding protein E3. Here, we report that infection of mouse primary keratinocytes with a vaccinia ΔE3L mutant virus triggers the production of beta interferon (IFN-β), interleukin-6 (IL-6), CCL4, and CCL5. None of these immune mediators is produced by keratinocytes infected with wild-type vaccinia virus. The dsRNA-binding domain of E3 suffices to prevent activation of the innate immune response. ΔE3L induction of IFN-β, IL-6, CCL4, and CCL5 secretion requires mitochondrial antiviral signaling protein (MAVS; an adaptor for the cytoplasmic viral RNA sensors RIG-I and MDA5) and the transcription factor IRF3. IRF3 phosphorylation is induced in keratinocytes infected with ΔE3L, an event that depends on MAVS. The response of keratinocytes to ΔE3L is unaffected by genetic ablation of Toll-like receptor 3 (TLR3), TRIF, TLR9, and MyD88.

scholarly journals The multi-functional reovirus σ3 protein is a virulence factor that suppresses stress granule formation and is associated with myocardial injury

2021 ◽  
Vol 17 (7) ◽  
pp. e1009494
Author(s):  
Yingying Guo ◽  
Meleana M. Hinchman ◽  
Mercedes Lewandrowski ◽  
Shaun T. Cross ◽  
Danica M. Sutherland ◽  
...  
Keyword(s):  
Viral Infection ◽  
Viral Entry ◽  
Post Infection ◽  
Rna Binding ◽  
Binding Capacity ◽  
Binding Activity ◽  
Dependent Manner ◽  
Viral Protein Synthesis ◽  
Granule Formation ◽  
Dsrna Binding

The mammalian orthoreovirus double-stranded (ds) RNA-binding protein σ3 is a multifunctional protein that promotes viral protein synthesis and facilitates viral entry and assembly. The dsRNA-binding capacity of σ3 correlates with its capacity to prevent dsRNA-mediated activation of protein kinase R (PKR). However, the effect of σ3 binding to dsRNA during viral infection is largely unknown. To identify functions of σ3 dsRNA-binding activity during reovirus infection, we engineered a panel of thirteen σ3 mutants and screened them for the capacity to bind dsRNA. Six mutants were defective in dsRNA binding, and mutations in these constructs cluster in a putative dsRNA-binding region on the surface of σ3. Two recombinant viruses expressing these σ3 dsRNA-binding mutants, K287T and R296T, display strikingly different phenotypes. In a cell-type dependent manner, K287T, but not R296T, replicates less efficiently than wild-type (WT) virus. In cells in which K287T virus demonstrates a replication deficit, PKR activation occurs and abundant stress granules (SGs) are formed at late times post-infection. In contrast, the R296T virus retains the capacity to suppress activation of PKR and does not mediate formation of SGs at late times post-infection. These findings indicate that σ3 inhibits PKR independently of its capacity to bind dsRNA. In infected mice, K287T produces lower viral titers in the spleen, liver, lungs, and heart relative to WT or R296T. Moreover, mice inoculated with WT or R296T viruses develop myocarditis, whereas those inoculated with K287T do not. Overall, our results indicate that σ3 functions to suppress PKR activation and subsequent SG formation during viral infection and that these functions correlate with virulence in mice.

Synergistic activation of transcription is mediated by the N-terminal domain of Drosophila fushi tarazu homeoprotein and can occur without DNA binding by the protein

1993 ◽  
Vol 13 (3) ◽  
pp. 1599-1609
Author(s):  
J Ananthan ◽  
R Baler ◽  
D Morrissey ◽  
J Zuo ◽  
Y Lan ◽  
...  
Keyword(s):  
Dna Binding ◽  
Protein Interactions ◽  
Binding Activity ◽  
Protein Protein Interactions ◽  
Fushi Tarazu ◽  
Combinatorial Regulation ◽  
Dna Binding Activity ◽  
Culture Cells ◽  
Synergistic Activation ◽  
Activation Of Transcription

Synergistic activation of transcription by Drosophila segmentation genes in tissue culture cells provides a model with which to study combinatorial regulation. We examined the synergistic activation of an engrailed-derived promoter by the pair-rule proteins paired (PRD) and fushi tarazu (FTZ). Synergistic activation by PRD requires regions of the homeodomain or adjacent sequences, and that by FTZ requires the first 171 residues. Surprisingly, deletion of the FTZ homeodomain does not reduce the capacity of the protein for synergistic activation, although this mutation abolishes any detectable DNA-binding activity. This finding suggests that FTZ can function through protein-protein interactions with PRD or other components of the homeoprotein transcription complex, adding a new layer of mechanisms that could underlie the functional specificities and combinatorial regulation of homeoproteins.

scholarly journals New Targets forZikaVirus Determined by Human-Viral Interactomic: A Bioinformatics Approach

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Eduardo Esteves ◽  
Nuno Rosa ◽  
Maria José Correia ◽  
Joel P. Arrais ◽  
Marlene Barros
Keyword(s):  
Immune Response ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Host Proteins ◽  
Zikv Infection ◽  
Antiviral Immune Response ◽  
Vesicular Traffic ◽  
Human Host ◽  
New Targets ◽  
Great Relevance

Identifying ZIKV factors interfering with human host pathways represents a major challenge in understanding ZIKV tropism and pathogenesis. The integration of proteomic, gene expression and Protein-Protein Interactions (PPIs) established between ZIKV and human host proteins predicted by the OralInt algorithm identified 1898 interactions with medium or high score (≥0.7). Targets implicated in vesicular traffic and docking were identified. New receptors involved in endocytosis pathways as ZIKV entry targets, using both clathrin-dependent (17 receptors) and independent (10 receptors) pathways, are described. New targets used by the ZIKV to undermine the host’s antiviral immune response are proposed based on predicted interactions established between the virus and host cell receptors and/or proteins with an effector or signaling role in the immune response such as IFN receptors and TLR. Complement and cytokines are proposed as extracellular potential interacting partners of the secreted form of NS1 ZIKV protein. Altogether, in this article, 18 new human targets for structural and nonstructural ZIKV proteins are proposed. These results are of great relevance for the understanding of viral pathogenesis and consequently the development of preventive (vaccines) and therapeutic targets for ZIKV infection management.

Sign in / Sign up

Export Citation Format

Share Document