scholarly journals Host ADP-ribosylation and the SARS-CoV-2 macrodomain

2021 ◽  
Author(s):  
Nicolas C. Hoch
Keyword(s):  
Innate Immunity ◽  
Viral Replication ◽  
Disease Severity ◽  
Protein Trafficking ◽  
Post Translational Modification ◽  
Adp Ribosylation ◽  
Open Questions ◽  
Parp Activity ◽  
Viral Target ◽  
Intense Research

The COVID-19 pandemic has prompted intense research efforts into elucidating mechanisms of coronavirus pathogenesis and to propose antiviral interventions. The interferon (IFN) response is the main antiviral component of human innate immunity and is actively suppressed by several non-structural SARS-CoV-2 proteins, allowing viral replication within human cells. Differences in IFN signalling efficiency and timing have emerged as central determinants of the variability of COVID-19 disease severity between patients, highlighting the need for an improved understanding of host–pathogen interactions that affect the IFN response. ADP-ribosylation is an underexplored post-translational modification catalyzed by ADP-ribosyl transferases collectively termed poly(ADP-ribose) polymerases (PARPs). Several human PARPs are induced by the IFN response and participate in antiviral defences by regulating IFN signalling itself, modulating host processes such as translation and protein trafficking, as well as directly modifying and inhibiting viral target proteins. SARS-CoV-2 and other viruses encode a macrodomain that hydrolyzes ADP-ribose modifications, thus counteracting antiviral PARP activity. This mini-review provides a brief overview of the known targets of IFN-induced ADP-ribosylation and the functions of viral macrodomains, highlighting several open questions in the field.

scholarly journals Androgen signaling uses a writer and a reader of ADP-ribosylation to regulate protein complex assembly

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chun-Song Yang ◽  
Kasey Jividen ◽  
Teddy Kamata ◽  
Natalia Dworak ◽  
Luke Oostdyk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Prostate Cancer Cells ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Complex Assembly ◽  
Adp Ribosylation ◽  
Signaling Axis ◽  
Regulate Protein ◽  
Protein Complex Assembly

AbstractAndrogen signaling through the androgen receptor (AR) directs gene expression in both normal and prostate cancer cells. Androgen regulates multiple aspects of the AR life cycle, including its localization and post-translational modification, but understanding how modifications are read and integrated with AR activity has been difficult. Here, we show that ADP-ribosylation regulates AR through a nuclear pathway mediated by Parp7. We show that Parp7 mono-ADP-ribosylates agonist-bound AR, and that ADP-ribosyl-cysteines within the N-terminal domain mediate recruitment of the E3 ligase Dtx3L/Parp9. Molecular recognition of ADP-ribosyl-cysteine is provided by tandem macrodomains in Parp9, and Dtx3L/Parp9 modulates expression of a subset of AR-regulated genes. Parp7, ADP-ribosylation of AR, and AR-Dtx3L/Parp9 complex assembly are inhibited by Olaparib, a compound used clinically to inhibit poly-ADP-ribosyltransferases Parp1/2. Our study reveals the components of an androgen signaling axis that uses a writer and reader of ADP-ribosylation to regulate protein-protein interactions and AR activity.

scholarly journals ADP-ribosylation of integrin α7 modulates the binding of integrin α7β1 to laminin

2004 ◽  
Vol 385 (1) ◽  
pp. 309-317 ◽  
Author(s):  
Zhefeng ZHAO ◽  
Joanna GRUSZCZYNSKA-BIEGALA ◽  
Anna ZOLKIEWSKA
Keyword(s):  
C2c12 Myotubes ◽  
Post Translational Modification ◽  
Integrin Β1 ◽  
Adp Ribosylation ◽  
In Vitro Binding ◽  
Vitro Binding ◽  
C2c12 Skeletal Muscle Cells ◽  
Adp Ribosyltransferase

The extracellular domain of integrin α7 is ADP-ribosylated by an arginine-specific ecto-ADP-ribosyltransferase after adding exogenous NAD+ to intact C2C12 skeletal muscle cells. The effect of ADP-ribosylation on the structure or function of integrin α7β1 has not been explored. In the present study, we show that ADP-ribosylation of integrin α7 takes place exclusively in differentiated myotubes and that this post-translational modification modulates the affinity of α7β1 dimer for its ligand, laminin. ADP-ribosylation in the 37-kDa ‘stalk’ region of α7 that takes place at micromolar NAD+ concentrations increases the binding of the α7β1 dimer to laminin. Increased in vitro binding of integrin α7β1 to laminin after ADP-ribosylation of the 37-kDa fragment of α7 requires the presence of Mn2+ and it is not observed in the presence of Mg2+. In contrast, ADP-ribosylation of the 63-kDa N-terminal region comprising the ligand-binding site of α7 that occurs at approx. 100 μM NAD+ inhibits the binding of integrin α7β1 to laminin. Furthermore, incubation of C2C12 myotubes with NAD+ increases the expression of an epitope on integrin β1 subunit recognized by monoclonal antibody 9EG7. We discuss our results based on the current models of integrin activation. We also hypothesize that ADP-ribosylation may represent a mechanism of regulation of integrin α7β1 function in myofibres in vivo when the continuity of the membrane is compromised and NAD+ is available as a substrate for ecto-ADP-ribosylation.

scholarly journals Recognition and inhibition of SARS-CoV-2 by humoral innate immunity pattern recognition molecules

2021 ◽  
Author(s):  
Matteo Stravalaci ◽  
Isabel Pagani ◽  
Elvezia Maria Paraboschi ◽  
Mattia Pedotti ◽  
Andrea Doni ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Innate Immunity ◽  
Disease Severity ◽  
Fluid Phase ◽  
Systematic Investigation ◽  
In Vitro Models ◽  
Lectin Pathway ◽  
Mannose Binding ◽  
Binding Lectin

The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in COVID-19. The present study was designed to conduct a systematic investigation of the interaction of humoral fluid phase pattern recognition molecules (PRM) with SARS-CoV-2. Out of 10 PRM tested, the long pentraxin PTX3 and Mannose Binding Lectin (MBL) bound the viral Nucleoprotein and Spike, respectively. MBL bound trimeric Spike, including that of variants of concern, in a glycan-dependent way and inhibited SARS-CoV-2 in three in vitro models. Moreover, upon binding to Spike, MBL activated the lectin pathway of complement activation. Genetic polymorphisms at the MBL locus were associated with disease severity. These results suggest that selected humoral fluid phase PRM can play an important role in resistance to, and pathogenesis of, COVID-19, a finding with translational implications.

Abstract 13527: Inhibition of With-No-Lysine Kinase Improves Right Ventricular Function by Blunting Excess Protein O-GlcNAcylation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Sasha Z Prisco ◽  
Megan Eklund ◽  
Kurt W Prins
Keyword(s):  
Cardiac Output ◽  
Right Ventricular ◽  
Vascular Disease ◽  
Disease Severity ◽  
Systolic Pressure ◽  
Fold Increase ◽  
Pulmonary Vascular Disease ◽  
Post Translational Modification ◽  
Loop Analysis ◽  
Rv Function

Introduction: Pulmonary arterial hypertension (PAH) is caused by obstructive remodeling of the pulmonary arteries which ultimately causes right ventricle (RV) failure and death. Increased expression of the glucose membrane transporters Glut1 and Glut4 occurs in the failing RV, but the upstream regulators of these proteins are unknown. The With-no-Lysine (WNK) kinase-1, a kinase activated in low chloride conditions, promotes expression of Glut1/4 in skeletal muscle, but its regulation in the RV in PAH is unexplored. Furthermore, the relationship between WNK1 and protein O-GlcNAcylation, a glucose based post-translational modification, has not been examined. Methods: Immunoblots quantified the abundance of WNK1, Glut1, Glut4, and total protein O-GlcNAcylation in the RV of control, monocrotaline (MCT) rats, and MCT rats treated with a WNK inhibitor two weeks after MCT injection. Echocardiography and pressure-volume loop analysis assessed RV function and pulmonary vascular disease severity. Results: Treatment with WNK inhibitor improved TAPSE (2.4±0.1 vs 1.8±0.1 mm, p =0.0007), cardiac output (86.0±9.1 vs 52.5±5.6 ml/min, p =0.02), and cardiac output normalized body weight (0.26±0.03 vs 0.15±0.02 ml/min/g, p =0.0032). Importantly, the WNK inhibitor did not alter pulmonary vascular disease severity as there were no differences in pulmonary artery acceleration time (18.2±1.5 vs 14.2±0.9 sec, p =0.22), Ea (0.58±0.07 vs 0.58±0.08 mmHg/μL, p=1.00), or right ventricular systolic pressure (71.8±7.6 vs 72.0±4.0 mmHg, p =1.00) compared to MCT. At the molecular level, WNK1 inhibition decreased expression of WNK1 (MCT: 1.3±0.2 fold increase, MCT-WNK: 3.4±2.2 fold decrease), Glut1 (MCT: 2.7±0.9 fold increase, MCT-WNK: 1.2±0.2 fold increase), Glut4 (MCT: 1.7±0.4 fold increase, MCT-WNK: 1.0±0.2 fold increase), and protein O-GlcNAcylation (MCT: 2.4±0.7 fold increase, MCT-WNK: 1.1±0.1 fold increase). Conclusions: WNK inhibition normalized Glut1/4 expression and protein O-GlcNAcylation in the RV. These molecular changes resulted in improved RV function without a change in pulmonary vascular disease burden.

ADP-ribosylation and intracellular traffic: an emerging role for PARP enzymes

2019 ◽  
Vol 47 (1) ◽  
pp. 357-370 ◽  
Author(s):  
Giovanna Grimaldi ◽  
Daniela Corda
Keyword(s):  
Intracellular Transport ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Intracellular Traffic ◽  
Adp Ribosylation ◽  
Cell Responses ◽  
Physiological Processes ◽  
Dependent Cell ◽  
Ribose Moiety

AbstractADP-ribosylation is an ancient and reversible post-translational modification (PTM) of proteins, in which the ADP-ribose moiety is transferred from NAD+ to target proteins by members of poly-ADP-ribosyl polymerase (PARP) family. The 17 members of this family have been involved in a variety of cellular functions, where their regulatory roles are exerted through the modification of specific substrates, whose identification is crucial to fully define the contribution of this PTM. Evidence of the role of the PARPs is now available both in the context of physiological processes and of cell responses to stress or starvation. An emerging role of the PARPs is their control of intracellular transport, as it is the case for tankyrases/PARP5 and PARP12. Here, we discuss the evidence pointing at this novel aspect of PARPs-dependent cell regulation.

scholarly journals Recognition of a glycosylation substrate by the O-GlcNAc transferase TPR repeats

Open Biology ◽  
2017 ◽  
Vol 7 (6) ◽  
pp. 170078 ◽  
Author(s):  
Karim Rafie ◽  
Olawale Raimi ◽  
Andrew T. Ferenbach ◽  
Vladimir S. Borodkin ◽  
Vaibhav Kapuria ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Substrate Specificity ◽  
Active Site ◽  
Target Site ◽  
Post Translational Modification ◽  
Tetratricopeptide Repeats ◽  
Protein Substrates ◽  
Nucleocytoplasmic Proteins ◽  
Glcnac Transferase ◽  
Single Enzyme

O-linked N -acetylglucosamine (O-GlcNAc) is an essential and dynamic post-translational modification found on hundreds of nucleocytoplasmic proteins in metazoa. Although a single enzyme, O-GlcNAc transferase (OGT), generates the entire cytosolic O-GlcNAc proteome, it is not understood how it recognizes its protein substrates, targeting only a fraction of serines/threonines in the metazoan proteome for glycosylation. We describe a trapped complex of human OGT with the C-terminal domain of TAB1, a key innate immunity-signalling O-GlcNAc protein, revealing extensive interactions with the tetratricopeptide repeats of OGT. Confirmed by mutagenesis, this interaction suggests that glycosylation substrate specificity is achieved by recognition of a degenerate sequon in the active site combined with an extended conformation C-terminal of the O-GlcNAc target site.

scholarly journals Structural and Functional Consequences Induced by Post-Translational Modifications in α-Defensins

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Enrico Balducci ◽  
Alessio Bonucci ◽  
Monica Picchianti ◽  
Rebecca Pogni ◽  
Eleonora Talluri
Keyword(s):  
Antimicrobial Peptide ◽  
Marked Change ◽  
Antibacterial Activities ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Adp Ribosylation ◽  
Functional Consequences ◽  
Adp Ribosyltransferase ◽  
Guanidino Group ◽  
Ribose Moiety

HNP-1 is an antimicrobial peptide that undergoes proteolytic cleavage to become a mature peptide. This process represents the mechanism commonly used by the cells to obtain a fully active antimicrobial peptide. In addition, it has been recently described that HNP-1 is recognized as substrate by the arginine-specific ADP-ribosyltransferase-1. Arginine-specific mono-ADP-ribosylation is an enzyme-catalyzed post-translational modification in which NAD+ serves as donor of the ADP-ribose moiety, which is transferred to the guanidino group of arginines in target proteins. While the arginine carries one positive charge, the ADP-ribose is negatively charged at the phosphate moieties at physiological pH. Therefore, the attachment of one or more ADP-ribose units results in a marked change of cationicity. ADP-ribosylation of HNP-1 drastically reduces its cytotoxic and antibacterial activities. While the chemotactic activity of HNP-1 remains unaltered, its ability to induce interleukin-8 production is enhanced. The arginine 14 of HNP-1 modified by the ADP-ribose is in some cases processed into ornithine, perhaps representing a different modality in the regulation of HNP-1 activities.

scholarly journals Post-Translational Modification Control of Innate Immunity

Immunity ◽  
2016 ◽  
Vol 45 (1) ◽  
pp. 15-30 ◽  
Author(s):  
Juan Liu ◽  
Cheng Qian ◽  
Xuetao Cao
Keyword(s):  
Innate Immunity ◽  
Post Translational Modification

scholarly journals Purification, characterization and molecular cloning of glycosylphosphatidylinositol-anchored arginine-specific ADP-ribosyltransferases from chicken

2005 ◽  
Vol 389 (3) ◽  
pp. 853-861 ◽  
Author(s):  
Masaharu Terashima ◽  
Harumi Osago ◽  
Nobumasa Hara ◽  
Yoshinori Tanigawa ◽  
Makoto Shimoyama ◽  
...  
Keyword(s):  
Molecular Cloning ◽  
Expression Patterns ◽  
Post Translational Modification ◽  
Rnase Protection ◽  
Functional Roles ◽  
Chicken Tissues ◽  
Adp Ribosylation ◽  
Real Time Quantitative Pcr ◽  
Specific Distribution ◽  
Rapid Amplification

Mono-ADP-ribosylation is a post-translational modification that regulates the functions of target proteins or peptides by attaching an ADP-ribose moiety. Here we report the purification, molecular cloning, characterization and tissue-specific distribution of novel arginine-specific Arts (ADP-ribosyltransferases) from chicken. Arts were detected in various chicken tissues as GPI (glycosylphosphatidylinositol)-anchored forms, and purified from the lung membrane fraction. By molecular cloning based on the partial amino acid sequence using 5′- and 3′-RACE (rapid amplification of cDNA ends), two full-length cDNAs of chicken GPI-anchored Arts, cgArt1 (chicken GPI-anchored Art1) and cgArt2, were obtained. The cDNA of cgArt1 encoded a novel polypeptide of 298 amino acids which shows a high degree of identity with cgArt2 (82.9%), Art6.1 (50.2%) and rabbit Art1 (42.1%). In contrast, the nucleotide sequence of cgArt2 was identical with that of Art7 cloned previously from chicken erythroblasts. cgArt1 and cgArt2 proteins expressed in DT40 cells were shown to be GPI-anchored Arts with a molecular mass of 45 kDa, and these Arts showed different enzymatic properties from the soluble chicken Art, Art6.1. RNase protection assays and real-time quantitative PCR revealed distinct expression patterns of the two Arts; cgArt1 was expressed predominantly in the lung, spleen and bone marrow, followed by the heart, kidney and muscle, while cgArt2 was expressed only in the heart and skeletal muscle. Thus GPI-anchored Arts encoded by the genes cgArt1 and cgArt2 are expressed extensively in chicken tissues. It may be worthwhile determining the functional roles of ADP-ribosylation in each tissue.

scholarly journals Viral macrodomains: a structural and evolutionary assessment of the pharmacological potential

Open Biology ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 200237 ◽  
Author(s):  
Johannes Gregor Matthias Rack ◽  
Valentina Zorzini ◽  
Zihan Zhu ◽  
Marion Schuller ◽  
Dragana Ahel ◽  
...  
Keyword(s):  
Virus Disease ◽  
Cross Reactivity ◽  
Structural Basis ◽  
Evolutionary Analysis ◽  
Structural Studies ◽  
Post Translational Modification ◽  
Necrosis Virus ◽  
Adp Ribosylation ◽  
Pharmacological Potential ◽  
And Function

Viral macrodomains possess the ability to counteract host ADP-ribosylation, a post-translational modification implicated in the creation of an antiviral environment via immune response regulation. This brought them into focus as promising therapeutic targets, albeit the close homology to some of the human macrodomains raised concerns regarding potential cross-reactivity and adverse effects for the host. Here, we evaluate the structure and function of the macrodomain of SARS-CoV-2, the causative agent of COVID-19. We show that it can antagonize ADP-ribosylation by PARP14, a cellular (ADP-ribosyl)transferase necessary for the restriction of coronaviral infections. Furthermore, our structural studies together with ligand modelling revealed the structural basis for poly(ADP-ribose) binding and hydrolysis, an emerging new aspect of viral macrodomain biology. These new insights were used in an extensive evolutionary analysis aimed at evaluating the druggability of viral macrodomains not only from the Coronaviridae but also Togaviridae and Iridoviridae genera (causing diseases such as Chikungunya and infectious spleen and kidney necrosis virus disease, respectively). We found that they contain conserved features, distinct from their human counterparts, which may be exploited during drug design.

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