bims-tunefa 2020-10-18 papers

bims-tunefa

Biomed News

on Tumor necrosis factor superfamily and post-translational modifications

Issue of 2020–10–18
seventeen papers selected by
John Silke, Walter and Eliza Hall Institute of Medical Research

Poxvirus-encoded TNF receptor homolog dampens inflammation and protects from uncontrolled lung pathology during respiratory infection.
NET formation - mechanisms and how they relate to other cell death pathways.
The dynamics of linear polyubiquitin.
Discovery of a Family of Mixed Lineage Kinase Domain-like Proteins in Plants and Their Role in Innate Immune Signaling.
Cytotoxic T cells swarm by homotypic chemokine signalling.
Regulation of ALT-associated homology-directed repair by polyADP-ribosylation.
Evidence for 28 genetic disorders discovered by combining healthcare and research data.
Non-canonical roles of NAMPT and PARP in inflammation.
The immune system on the TRAIL of Alzheimer's disease.
Engineering Af1521 improves ADP-ribose binding and identification of ADP-ribosylated proteins.
PolyADP-Ribosylation of NFATc3 and NF-κB Transcription Factors Modulate Macrophage Inflammatory Gene Expression in LPS-Induced Acute Lung Injury.
Clearance of Apoptotic cells by Lung Alveolar Macrophages Prevents Development of House Dust Mite-induced Asthmatic Lung Inflammation.
How Bilayer Properties Influence Membrane Protein Folding.
Open Targets Genetics: systematic identification of trait-associated genes using large-scale genetics and functional genomics.
Suppressing PARylation by 2',5'-oligoadenylate synthetase 1 inhibits DNA damage-induced cell death.
RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer.
Coronavirus infection and PARP expression dysregulate the NAD Metabolome: an actionable component of innate immunity.

Proc Natl Acad Sci U S A. 2020 Oct 12. pii: 202004688. [Epub ahead of print]

Poxvirus-encoded TNF receptor homolog dampens inflammation and protects from uncontrolled lung pathology during respiratory infection.

Zahrah Al Rumaih, Ma Junaliah Tuazon Kels, Esther Ng, Pratikshya Pandey, Sergio M Pontejo, Alí Alejo, Antonio Alcamí, Geeta Chaudhri, Gunasegaran Karupiah.

  Ectromelia virus (ECTV) causes mousepox, a surrogate mouse model for smallpox caused by variola virus in humans. Both orthopoxviruses encode tumor necrosis factor receptor (TNFR) homologs or viral TNFR (vTNFR). These homologs are termed cytokine response modifier (Crm) proteins, containing a TNF-binding domain and a chemokine-binding domain called smallpox virus-encoded chemokine receptor (SECRET) domain. ECTV encodes one vTNFR known as CrmD. Infection of ECTV-resistant C57BL/6 mice with a CrmD deletion mutant virus resulted in uniform mortality due to excessive TNF secretion and dysregulated inflammatory cytokine production. CrmD dampened pathology, leukocyte recruitment, and inflammatory cytokine production in lungs including TNF, IL-6, IL-10, and IFN-γ. Blockade of TNF, IL-6, or IL-10R function with monoclonal antibodies reduced lung pathology and provided 60 to 100% protection from otherwise lethal infection. IFN-γ caused lung pathology only when both the TNF-binding and SECRET domains were absent. Presence of the SECRET domain alone induced significantly higher levels of IL-1β, IL-6, and IL-10, likely overcoming any protective effects that might have been afforded by anti-IFN-γ treatment. The use of TNF-deficient mice and those that express only membrane-associated but not secreted TNF revealed that CrmD is critically dependent on host TNF for its function. In vitro, recombinant Crm proteins from different orthopoxviruses bound to membrane-associated TNF and dampened inflammatory gene expression through reverse signaling. CrmD does not affect virus replication; however, it provides the host advantage by enabling survival. Host survival would facilitate virus spread, which would also provide an advantage to the virus.

Keywords:  CrmD inhibits inflammation; cytokine response modifier D; cytokine storm; lung pathology and pneumonia; respiratory viral infection

DOI:  https://doi.org/10.1073/pnas.2004688117
FEBS J. 2020 Oct 12.

NET formation - mechanisms and how they relate to other cell death pathways.

Thibault Rosazza, Jordan Warner, Gabriel Sollberger.

  Cell death is an integral part of both infectious and sterile inflammatory reactions. Many cell death pathways cause the dying cell to lyse, thereby amplifying inflammation. A special form of lytic cell death is the formation of neutrophil extracellular traps (NETs), large structures of chromatin and antimicrobial proteins, which are released by dying neutrophils to capture extracellular pathogens and limit the spread of infections. The molecular mechanisms of NET formation remain incompletely understood. Recent research demonstrated substantial crosstalk between different cell death pathways, most notably between apoptosis, pyroptosis and necroptosis. Here we review suicidal as well as vital NET formation and discuss potential crosstalk of their mechanisms of release with other forms of cell death.

Keywords:  NET formation; Neutrophils; cell death; inflammation; innate immunity

DOI:  https://doi.org/10.1111/febs.15589
Sci Adv. 2020 Oct;pii: eabc3786. [Epub ahead of print]6(42):

The dynamics of linear polyubiquitin.

Alexander Jussupow, Ana C Messias, Ralf Stehle, Arie Geerlof, Sara M Ø Solbak, Cristina Paissoni, Anders Bach, Michael Sattler, Carlo Camilloni.

Polyubiquitin chains are flexible multidomain proteins, whose conformational dynamics enable them to regulate multiple biological pathways. Their dynamic is determined by the linkage between ubiquitins and by the number of ubiquitin units. Characterizing polyubiquitin behavior as a function of their length is hampered because of increasing system size and conformational variability. Here, we introduce a new approach to efficiently integrating small-angle x-ray scattering with simulations allowing us to accurately characterize the dynamics of linear di-, tri-, and tetraubiquitin in the free state as well as of diubiquitin in complex with NEMO, a central regulator in the NF-κB pathway. Our results show that the behavior of the diubiquitin subunits is independent of the presence of additional ubiquitin modules and that the dynamics of polyubiquitins with different lengths follow a simple model. Together with experimental data from multiple biophysical techniques, we then rationalize the 2:1 NEMO:polyubiquitin binding.

DOI: https://doi.org/10.1126/sciadv.abc3786
Cell Host Microbe. 2020 Sep 30. pii: S1931-3128(20)30467-4. [Epub ahead of print]

Discovery of a Family of Mixed Lineage Kinase Domain-like Proteins in Plants and Their Role in Innate Immune Signaling.

Lisa K Mahdi, Menghang Huang, Xiaoxiao Zhang, Ryohei Thomas Nakano, Leïla Brulé Kopp, Isabel M L Saur, Florence Jacob, Viera Kovacova, Dmitry Lapin, Jane E Parker, James M Murphy, Kay Hofmann, Paul Schulze-Lefert, Jijie Chai, Takaki Maekawa.

  HeLo domain-containing mixed lineage kinase domain-like protein (MLKL), a pseudokinase, mediates necroptotic cell death in animals. Here, we report the discovery of a conserved protein family across seed plants that structurally resembles vertebrate MLKL. The Arabidopsis genome encodes three MLKLs (AtMLKLs) with overlapping functions in disease resistance mediated by Toll-interleukin 1-receptor domain intracellular immune receptors (TNLs). The HeLo domain of AtMLKLs confers cell death activity but is dispensable for immunity. Cryo-EM structures reveal a tetrameric configuration, in which the HeLo domain is buried, suggestive of an auto-repressed complex. The mobility of AtMLKL1 along microtubules is reduced by chitin, a fungal immunity-triggering molecule. An AtMLKL1 phosphomimetic variant exhibiting reduced mobility enhances immunity. Coupled with the predicted presence of HeLo domains in plant helper NLRs, our data reveal the importance of HeLo domain proteins for TNL-dependent immunity and argue for a cell death-independent immune mechanism mediated by MLKLs.

Keywords:  Cell death; HeLo domain; MLKL; cryo-electron microscopy structures; microtubules; necroptosis; toll-interleukin1-receptor domain intracellular immune receptors

DOI:  https://doi.org/10.1016/j.chom.2020.08.012
Elife. 2020 Oct 13. pii: e56554. [Epub ahead of print]9

Cytotoxic T cells swarm by homotypic chemokine signalling.

Jorge Luis Galeano Niño, Sophie V Pageon, Szun S Tay, Feyza Colakoglu, Daryan Kempe, Jack Hywood, Jessica K Mazalo, James Cremasco, Matt A Govendir, Laura F Dagley, Kenneth Hsu, Simone Rizzetto, Jerzy Zieba, Gregory Rice, Victoria Prior, Geraldine M O'Neill, Richard J Williams, David R Nisbet, Belinda Kramer, Andrew I Webb, Fabio Luciani, Mark N Read, Maté Biro.

  Cytotoxic T lymphocytes (CTLs) are thought to arrive at target sites either via random search or following signals by other leukocytes. Here, we reveal independent emergent behaviour in CTL populations attacking tumour masses. Primary murine CTLs coordinate their migration in a process reminiscent of the swarming observed in neutrophils. CTLs engaging cognate targets accelerate the recruitment of distant T cells through long-range homotypic signalling, in part mediated via the diffusion of chemokines CCL3 and CCL4. Newly arriving CTLs augment the chemotactic signal, further accelerating mass recruitment in a positive feedback loop. Activated effector human T cells and chimeric antigen receptor (CAR) T cells similarly employ intra-population signalling to drive rapid convergence. Thus, CTLs recognising a cognate target can induce a localised mass response by amplifying the direct recruitment of additional T cells independently of other leukocytes.

Keywords:  computational biology; human; immunology; inflammation; mouse; systems biology

DOI:  https://doi.org/10.7554/eLife.56554
Nat Struct Mol Biol. 2020 Oct 12.

Regulation of ALT-associated homology-directed repair by polyADP-ribosylation.

Song My Hoang, Nicole Kaminski, Ragini Bhargava, Jonathan Barroso-González, Michelle L Lynskey, Laura García-Expósito, Justin L Roncaioli, Anne R Wondisford, Callen T Wallace, Simon C Watkins, Dominic I James, Ian D Waddell, Donald Ogilvie, Kate M Smith, Felipe da Veiga Leprevost, Dattatreya Mellacharevu, Alexey I Nesvizhskii, Jianfeng Li, Dominique Ray-Gallet, Robert W Sobol, Genevieve Almouzni, Roderick J O'Sullivan.

The synthesis of poly(ADP-ribose) (PAR) reconfigures the local chromatin environment and recruits DNA-repair complexes to damaged chromatin. PAR degradation by poly(ADP-ribose) glycohydrolase (PARG) is essential for progression and completion of DNA repair. Here, we show that inhibition of PARG disrupts homology-directed repair (HDR) mechanisms that underpin alternative lengthening of telomeres (ALT). Proteomic analyses uncover a new role for poly(ADP-ribosyl)ation (PARylation) in regulating the chromatin-assembly factor HIRA in ALT cancer cells. We show that HIRA is enriched at telomeres during the G2 phase and is required for histone H3.3 deposition and telomere DNA synthesis. Depletion of HIRA elicits systemic death of ALT cancer cells that is mitigated by re-expression of ATRX, a protein that is frequently inactivated in ALT tumors. We propose that PARylation enables HIRA to fulfill its essential role in the adaptive response to ATRX deficiency that pervades ALT cancers.

DOI: https://doi.org/10.1038/s41594-020-0512-7
Nature. 2020 Oct 14.

Evidence for 28 genetic disorders discovered by combining healthcare and research data.

Deciphering Developmental Disorders Study

De novo mutations in protein-coding genes are a well-established cause of developmental disorders1. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations1,2. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent-offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders.

DOI: https://doi.org/10.1038/s41586-020-2832-5
Dev Comp Immunol. 2020 Oct 07. pii: S0145-305X(20)30436-5. [Epub ahead of print] 103881

Non-canonical roles of NAMPT and PARP in inflammation.

Francisco J Martínez-Morcillo, Joaquín Cantón-Sandoval, Teresa Martínez-Menchón, Raúl Corbalán-Vélez, Pablo Mesa-Del-Castillo, Ana B Pérez-Oliva, Diana García-Moreno, Victoriano Mulero.

  Nicotinamide adenine dinucleotide (NAD+) is the most important hydrogen carrier in cell redox reactions. It is involved in mitochondrial function and metabolism, circadian rhythm, the immune response and inflammation, DNA repair, cell division, protein-protein signaling, chromatin remodeling and epigenetics. Recently, NAD+ has been recognized as the molecule of life, since, by increasing NAD+ levels in old or sick animals, it is possible to improve their health and lengthen their lifespan. In this review, we summarize the contribution of NAD+ metabolism to inflammation, with special emphasis in the major NAD+ biosynthetic enzyme, nicotinamide phosphoribosyl transferase (NAMPT), and the NAD+-consuming enzyme, poly(ADP-ribose) polymerase (PARP). The extracurricular roles of these enzymes, i.e. the proinflammatory role of NAMPT after its release, and the ability of PARP to promote a novel form of cell death, known as parthanatos, upon hyperactivation are revised and discussed in the context of several chronic inflammatory diseases.

Keywords:  NAD(+); NAMPT; PARP; chronic inflammation; immunity; parthanatos

DOI:  https://doi.org/10.1016/j.dci.2020.103881
J Neuroinflammation. 2020 Oct 13. 17(1): 298

The immune system on the TRAIL of Alzheimer's disease.

Chiara Burgaletto, Antonio Munafò, Giulia Di Benedetto, Cettina De Francisci, Filippo Caraci, Rosaria Di Mauro, Claudio Bucolo, Renato Bernardini, Giuseppina Cantarella.

  Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive degeneration and loss of neurons in specific regions of the central nervous system. Chronic activation of the immune cells resident in the brain, peripheral immune cell trafficking across the blood-brain barrier, and release of inflammatory and neurotoxic factors, appear critical contributors of the neuroinflammatory response that drives the progression of neurodegenerative processes in AD. As the neuro-immune network is impaired in course of AD, this review is aimed to point out the essential supportive role of innate and adaptive immune response either in normal brain as well as in brain recovery from injury. Since a fine-tuning of the immune response appears crucial to ensure proper nervous system functioning, we focused on the role of the TNF superfamily member, TNF-related apoptosis-inducing ligand (TRAIL), which modulates both the innate and adaptive immune response in the pathogenesis of several immunological disorders and, in particular, in AD-related neuroinflammation. We here summarized mounting evidence of potential involvement of TRAIL signaling in AD pathogenesis, with the aim to provide clearer insights about potential novel therapeutic approaches in AD.

Keywords:  Immune response; Neuroinflammation; Proinflammatory cytokines; Regulatory T cells

DOI:  https://doi.org/10.1186/s12974-020-01968-1
Nat Commun. 2020 10 15. 11(1): 5199

Engineering Af1521 improves ADP-ribose binding and identification of ADP-ribosylated proteins.

Kathrin Nowak, Florian Rosenthal, Tobias Karlberg, Mareike Bütepage, Ann-Gerd Thorsell, Birgit Dreier, Jonas Grossmann, Jens Sobek, Ralph Imhof, Bernhard Lüscher, Herwig Schüler, Andreas Plückthun, Deena M Leslie Pedrioli, Michael O Hottiger.

Protein ADP-ribosylation is a reversible post-translational modification that regulates important cellular functions. The identification of modified proteins has proven challenging and has mainly been achieved via enrichment methodologies. Random mutagenesis was used here to develop an engineered Af1521 ADP-ribose binding macro domain protein with 1000-fold increased affinity towards ADP-ribose. The crystal structure reveals that two point mutations K35E and Y145R form a salt bridge within the ADP-ribose binding domain. This forces the proximal ribose to rotate within the binding pocket and, as a consequence, improves engineered Af1521 ADPr-binding affinity. Its use in our proteomic ADP-ribosylome workflow increases the ADP-ribosylated protein identification rates and yields greater ADP-ribosylome coverage. Furthermore, generation of an engineered Af1521 Fc fusion protein confirms the improved detection of cellular ADP-ribosylation by immunoblot and immunofluorescence. Thus, this engineered isoform of Af1521 can also serve as a valuable tool for the analysis of cellular ADP-ribosylation under in vivo conditions.

DOI: https://doi.org/10.1038/s41467-020-18981-w
J Innate Immun. 2020 Oct 12. 1-11

PolyADP-Ribosylation of NFATc3 and NF-κB Transcription Factors Modulate Macrophage Inflammatory Gene Expression in LPS-Induced Acute Lung Injury.

Yunjuan Nie, Teja Srinivas Nirujogi, Ravi Ranjan, Brenda F Reader, Sangwoon Chung, Megan N Ballinger, Joshua A Englert, John W Christman, Manjula Karpurapu.

  Pulmonary macrophages play a critical role in the recognition of pathogens, initiation of host defense via inflammation, clearance of pathogens from the airways, and resolution of inflammation. Recently, we have shown a pivotal role for the nuclear factor of activated T-cell cytoplasmic member 3 (NFATc3) transcription factor in modulating pulmonary macrophage function in LPS-induced acute lung injury (ALI) pathogenesis. Although the NFATc proteins are activated primarily by calcineurin-dependent dephosphorylation, here we show that LPS induces posttranslational modification of NFATc3 by polyADP-ribose polymerase 1 (PARP-1)-mediated polyADP-ribosylation. ADP-ribosylated NFATc3 showed increased binding to iNOS and TNFα promoter DNA, thereby increasing downstream gene expression. Inhibitors of PARP-1 decreased LPS-induced NFATc3 ribosylation, target gene promoter binding, and gene expression. LPS increased NFAT luciferase reporter activity in lung macrophages and lung tissue that was inhibited by pretreatment with PARP-1 inhibitors. More importantly, pretreatment of mice with the PARP-1 inhibitor olaparib markedly decreased LPS-induced cytokines, protein extravasation in bronchoalveolar fluid, lung wet-to-dry ratios, and myeloperoxidase activity. Furthermore, PARP-1 inhibitors decreased NF-кB luciferase reporter activity and LPS-induced ALI in NF-кB reporter mice. Thus, our study demonstrates that inhibiting NFATc3 and NF-кB polyADP-ribosylation with PARP-1 inhibitors prevented LPS-induced ALI pathogenesis.

Keywords:   NFATc3; Acute lung injury; Macrophage; PolyADP-ribose polymerase 1; Pulmonary edema

DOI:  https://doi.org/10.1159/000510269
J Allergy Clin Immunol. 2020 Oct 13. pii: S0091-6749(20)31406-8. [Epub ahead of print]

Clearance of Apoptotic cells by Lung Alveolar Macrophages Prevents Development of House Dust Mite-induced Asthmatic Lung Inflammation.

Haruka Miki, Hong Pei, Donald Tom Gracias, Joel Linden, Michael Croft.

   BACKGROUND: Poor clearance of apoptotic cells has been suggested to contribute to severe asthma, but whether uptake of apoptotic cells by lung phagocytes might dampen House Dust Mite (HDM)-induced lung inflammation has not been shown.
OBJECTIVE: We investigated if apoptotic cell engulfment in the murine lung impacts the development of allergen-induced asthmatic airway inflammation and which immune modulating mechanisms were activated.
METHODS: Apoptotic cells were infused into the lungs of mice challenged with HDM allergen and lung inflammation, expression of suppressive molecules, and induction of Treg were monitored. Additionally, an adenosine receptor agonist was tested to study the mechanism of suppression elicited by apoptotic cells.
RESULTS: Apoptotic cell uptake by lung alveolar macrophages suppressed HDM-driven allergic asthma. This was associated with promoting the Treg-inducing molecule retinoic acid, inhibiting inflammatory cytokine production, and making macrophages more susceptible to receiving suppressive signals from adenosine. Correspondingly, adenosine receptor agonist treatment also limited HDM-driven allergic airway inflammation through an action on alveolar macrophages.
CONCLUSION: These data provide insight into the mechanisms by which lung macrophages dampen allergen-induced airway inflammation. They suggest that targeting lung macrophages to increase their phagocytic capacity, enhance their ability to make retinoic acid, dampen their capacity to make inflammatory cytokines, and increase their responsiveness to adenosine, could be useful to suppress allergic responses.

Keywords:  Adenosine; Alveolar macrophage; Apoptotic cell clearance; Asthma; Regulatory T cell

DOI:  https://doi.org/10.1016/j.jaci.2020.10.005
Protein Sci. 2020 Oct 15.

How Bilayer Properties Influence Membrane Protein Folding.

Karolina Corin, James U Bowie.

  The question of how proteins manage to organize into a unique three-dimensional structure has been a major field of study since the first protein structures were determined. For membrane proteins, the question is made more complex because, unlike water-soluble proteins, the solvent is not homogenous or even unique. Each cell and organelle has a distinct lipid composition that can change in response to environmental stimuli. Thus, the study of membrane protein folding requires not only understanding how the unfolded chain navigates its way to the folded state, but also how changes in bilayer properties can affect that search. Here we review what we know so far about the impact of lipid composition on bilayer physical properties and how those properties can affect folding. A better understanding of the lipid bilayer and its effects on membrane protein folding is not only important for a theoretical understanding of the folding process, but can also have a practical impact on our ability to work with and design membrane proteins. This article is protected by copyright. All rights reserved.

Keywords:  lipids; membrane insertion; packing pressure; phospholipids; reconstitution; stability; topology

DOI:  https://doi.org/10.1002/pro.3973
Nucleic Acids Res. 2020 Oct 12. pii: gkaa840. [Epub ahead of print]

Open Targets Genetics: systematic identification of trait-associated genes using large-scale genetics and functional genomics.

Maya Ghoussaini, Edward Mountjoy, Miguel Carmona, Gareth Peat, Ellen M Schmidt, Andrew Hercules, Luca Fumis, Alfredo Miranda, Denise Carvalho-Silva, Annalisa Buniello, Tony Burdett, James Hayhurst, Jarrod Baker, Javier Ferrer, Asier Gonzalez-Uriarte, Simon Jupp, Mohd Anisul Karim, Gautier Koscielny, Sandra Machlitt-Northen, Cinzia Malangone, Zoe May Pendlington, Paola Roncaglia, Daniel Suveges, Daniel Wright, Olga Vrousgou, Eliseo Papa, Helen Parkinson, Jacqueline A L MacArthur, John A Todd, Jeffrey C Barrett, Jeremy Schwartzentruber, David G Hulcoop, David Ochoa, Ellen M McDonagh, Ian Dunham.

Open Targets Genetics (https://genetics.opentargets.org) is an open-access integrative resource that aggregates human GWAS and functional genomics data including gene expression, protein abundance, chromatin interaction and conformation data from a wide range of cell types and tissues to make robust connections between GWAS-associated loci, variants and likely causal genes. This enables systematic identification and prioritisation of likely causal variants and genes across all published trait-associated loci. In this paper, we describe the public resources we aggregate, the technology and analyses we use, and the functionality that the portal offers. Open Targets Genetics can be searched by variant, gene or study/phenotype. It offers tools that enable users to prioritise causal variants and genes at disease-associated loci and access systematic cross-disease and disease-molecular trait colocalization analysis across 92 cell types and tissues including the eQTL Catalogue. Data visualizations such as Manhattan-like plots, regional plots, credible sets overlap between studies and PheWAS plots enable users to explore GWAS signals in depth. The integrated data is made available through the web portal, for bulk download and via a GraphQL API, and the software is open source. Applications of this integrated data include identification of novel targets for drug discovery and drug repurposing.

DOI: https://doi.org/10.1093/nar/gkaa840
EMBO J. 2020 Oct 15. 39(20): e106593

Suppressing PARylation by 2',5'-oligoadenylate synthetase 1 inhibits DNA damage-induced cell death.

Anna Kondratova, HyeonJoo Cheon, Beihua Dong, Elise G Holvey-Bates, Metis Hasipek, Irina Taran, Christina Gaughan, Babal K Jha, Robert H Silverman, George R Stark.

DOI: https://doi.org/10.15252/embj.2020106593
Cancer Cell. 2020 Oct 12. pii: S1535-6108(20)30494-3. [Epub ahead of print]38(4): 585-590

RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer.

Wei Wang, Jill M Marinis, Allison M Beal, Shivraj Savadkar, Yue Wu, Mohammed Khan, Pardeep S Taunk, Nan Wu, Wenyu Su, Jingjing Wu, Aarif Ahsan, Emma Kurz, Ting Chen, Inedouye Yaboh, Fei Li, Johana Gutierrez, Brian Diskin, Mautin Hundeyin, Michael Reilly, John D Lich, Philip A Harris, Mukesh K Mahajan, James H Thorpe, Pamela Nassau, Julie E Mosley, Joshua Leinwand, Juan A Kochen Rossi, Ankita Mishra, Berk Aykut, Michael Glacken, Atsuo Ochi, Narendra Verma, Jacqueline I Kim, Varshini Vasudevaraja, Dennis Adeegbe, Christina Almonte, Ece Bagdatlioglu, Deirdre J Cohen, Kwok-Kin Wong, John Bertin, George Miller.

DOI: https://doi.org/10.1016/j.ccell.2020.09.020
J Biol Chem. 2020 Oct 13. pii: jbc.RA120.015138. [Epub ahead of print]

Coronavirus infection and PARP expression dysregulate the NAD Metabolome: an actionable component of innate immunity.

Collin D Heer, Daniel J Sanderson, Lynden S Voth, Yousef M O Alhammad, Mark S Schmidt, Samuel A J Trammell, Stanley Perlman, Michael S Cohen, Anthony R Fehr, Charles Brenner.

  Poly-ADP-ribose polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using nicotinamide adenine dinucleotide (NAD) as the source of ADPR. While the well-known poly-ADP-ribosylating (PARylating) PARPs primarily function in the DNA damage response, many non-canonical mono-ADP-ribosylating (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust upregulation of several PARPs following infection with Murine Hepatitis Virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly upregulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while downregulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD+ and NADP+ Finally, we show that NAMPT activation, NAM and NR dramatically decrease the replication of an MHV virus that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD, and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses.

Keywords:  COVID-19; NAD biosynthesis; PARP; RNAseq; SARS-CoV-2; gene transcription; interferon; plus-stranded RNA virus; post-translational modification (PTM)

DOI:  https://doi.org/10.1074/jbc.RA120.015138