The coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression

Grunewald, Matthew; Chen, Yating; Kuny, Chad V.; Maejima, Takashi; Lease, Robert; Ferraris, Dana; Aikawa, Masamichi; Sullivan, Christopher S.; Perlman, Stanley; Fehr, Anthony R.

doi:10.1371/journal.ppat.1007756

Cited by 179 publications

(312 citation statements)

References 82 publications

(127 reference statements)

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“…Initial control of SINV replication in the CNS is dependent on the innate immune response, particularly local production of type I IFN (77)(78)(79). Because viral MDs can influence both the induction of and the response to innate immune effectors (40,65,80,81), we assessed multiple parameters of the immune response to SINV in the CNSs of infected mice. Mice infected with Y114A in general had similar CNS levels of IFN-␣ and IFN-␤ and greater induction of ISGs Parp9, -10, -12, -13, and -14; Ifit1 and -2; and Isg15 ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Effects of nsP3 MD mutations on expression of Parp mRNAs in the CNS. Several PARPs are under diversifying evolutionary pressure, are induced by IFN, and/or have demonstrated antiviral activity, suggesting that MD function may be important for countering the antiviral effects of ADP-ribosylated proteins (46,50,51,64,65). In addition, although Parp mRNAs are not induced by infection of NSC34 cells, PARPs are activated for ADP-ribosylation and facilitate CHIKV replication (37).…”

Section: Effects Of Nsp3 MD Mutations On Cns Virus Replication and Clmentioning

confidence: 99%

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Both ADP-Ribosyl-Binding and Hydrolase Activities of the Alphavirus nsP3 Macrodomain Affect Neurovirulence in Mice

Abraham

McPherson

Dasovich

et al. 2020

mBio

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Macrodomain (MD), a highly conserved protein fold present in a subset of plus-strand RNA viruses, binds to and hydrolyzes ADP-ribose (ADPr) from ADPribosylated proteins. ADPr-binding by the alphavirus nonstructural protein 3 (nsP3) MD is necessary for the initiation of virus replication in neural cells, whereas hydrolase activity facilitates replication complex amplification. To determine the importance of these activities for pathogenesis of alphavirus encephalomyelitis, mutations were introduced into the nsP3 MD of Sindbis virus (SINV), and the effects on ADPr binding and hydrolase activities, virus replication, immune responses, and disease were assessed. Elimination of ADPr-binding and hydrolase activities (G32E) severely impaired in vitro replication of SINV in neural cells and in vivo replication in the central nervous systems of 2-week-old mice with reversion to wild type (WT) (G) or selection of a less compromising change (S) during replication. SINVs with decreased binding and hydrolase activities (G32S and G32A) or with hydrolase deficiency combined with better ADPr-binding (Y114A) were less virulent than WT virus. Compared to the WT, the G32S virus replicated less well in both the brain and spinal cord, induced similar innate responses, and caused less severe disease with full recovery of survivors, whereas the Y114A virus replicated well, induced higher expression of interferon-stimulated and NF-B-induced genes, and was cleared more slowly from the spinal cord with persistent paralysis in survivors. Therefore, MD function was important for neural cell replication both in vitro and in vivo and determined the outcome from alphavirus encephalomyelitis in mice. IMPORTANCE Viral encephalomyelitis is an important cause of long-term disability, as well as acute fatal disease. Identifying viral determinants of outcome helps in assessing disease severity and developing new treatments. Mosquito-borne alphaviruses infect neurons and cause fatal disease in mice. The highly conserved macrodomain of nonstructural protein 3 binds and can remove ADP-ribose (ADPr) from ADPribosylated proteins. To determine the importance of these functions for virulence, recombinant mutant viruses were produced. If macrodomain mutations eliminated ADPr-binding or hydrolase activity, viruses did not grow. If the binding and hydrolase activities were impaired, the viruses grew less well than the wild-type virus, induced similar innate responses, and caused less severe disease, and most of the infected mice recovered. If binding was improved, but hydrolase activity was decreased, the virus replicated well and induced greater innate responses than did the WT, but clearance from the nervous system was impaired, and mice remained paralyzed. Therefore, macrodomain function determined the outcome of alphavirus encephalomyelitis. Citation Abraham R, McPherson RL, Dasovich M, Badiee M, Leung AKL, Griffin DE. 2020. Both ADP-ribosyl-binding and hydrolase activities of the alphavirus nsP3 macrodomain affect neurovirulence in mice. mBio 11:e03253-1...

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Section: Discussionmentioning

confidence: 99%

Section: Effects Of Nsp3 MD Mutations On Cns Virus Replication and Clmentioning

confidence: 99%

Both ADP-Ribosyl-Binding and Hydrolase Activities of the Alphavirus nsP3 Macrodomain Affect Neurovirulence in Mice

Abraham

McPherson

Dasovich

et al. 2020

mBio

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“…First, many mammalian PARPs are stimulated by the production of IFN (IFN-stimulated genes [ISGs]), and thus are part of the mammalian antiviral defense system (Atasheva et al 2012;Zhang et al 2015;Eckei et al 2017;Li et al 2018;Grunewald et al 2019a). Also, several mono-ADP-ribosylating PARPs are rapidly evolving, indicating ongoing conflict with pathogens.…”

Section: Mammalian Parps Display Several Properties Indicative Of Invmentioning

confidence: 99%

“…Recent studies using chikungunya virus (CHIKV) macrodomain mutants showed that macrodomain ADP-ribose binding facilitated initiation of virus replication, while hydrolase activity was essential for the amplification of replication complexes (Abraham et al 2018). Infection with ADP-ribosylhydrolase (ARH)-deficient CoVs, including severe acute respiratory syndrome (SARS)-CoV and murine hepatitis virus (MHV), led to higher levels of IFN and other cytokines, indicating that it may block the innate immune response (Fehr et al 2016;Grunewald et al 2019a). The ARH-deficient MHV replicates poorly in primary macrophages, and importantly, this defect could be partially rescued by PARP inhibitors, directly indicating PARPs in the antiviral response to CoVs (Grunewald et al 2019a).…”

Section: Some Virus Families Encode For a Macrodomain Protein That Rementioning

confidence: 99%

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

et al. 2020

Self Cite

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Poly-adenosine diphosphate-ribose polymerases (PARPs) promote ADP-ribosylation, a highly conserved, fundamental posttranslational modification (PTM). PARP catalytic domains transfer the ADP-ribose moiety from NAD+ to amino acid residues of target proteins, leading to mono- or poly-ADP-ribosylation (MARylation or PARylation). This PTM regulates various key biological and pathological processes. In this review, we focus on the roles of the PARP family members in inflammation and host–pathogen interactions. Here we give an overview the current understanding of the mechanisms by which PARPs promote or suppress proinflammatory activation of macrophages, and various roles PARPs play in virus infections. We also demonstrate how innovative technologies, such as proteomics and systems biology, help to advance this research field and describe unanswered questions.

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“…By reversing defensive host ADPr mechanisms, viral macrodomains have been reported to support replication of viruses and their pathogenic mechanisms, thus leading to evasion of the host immune response [33,35,185]. Of note, macrodomain-containing hydrolases encoded by members of Coronaviruses (CoVs) have been also reported to modulate the production of interferon by erasing the ADPrdependent signalling of the host that is required for interferon induction [186]. For further details about viral macrodomains, we refer the reader to valuable and specialised reviews in the field [33,35,185].…”

Section: Adp-ribosyl Hydrolasesmentioning

confidence: 99%

Targeting ADP-ribosylation as an antimicrobial strategy

Catara

Corteggio

Valente

et al. 2019

Biochemical Pharmacology

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A B S T R A C T ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules controlling major biological processes as diverse as DNA damage repair, transcriptional regulation, intracellular transport, immune and stress responses, cell survival and proliferation. Furthermore, enzymatic reactions of ADPr are central in the pathogenesis of many human diseases, including infectious conditions. By providing a review of ADPr signalling in bacterial systems, we highlight the relevance of this chemical modification in the pathogenesis of human diseases depending on host-pathogen interactions. The post-antibiotic era has raised the need to find alternative approaches to antibiotic administration, as major pathogens becoming resistant to antibiotics. An in-depth understanding of ADPr reactions provides the rationale for designing novel antimicrobial strategies for treatment of infectious diseases. In addition, the understanding of mechanisms of ADPr by bacterial virulence factors offers important hints to improve our knowledge on cellular processes regulated by eukaryotic homologous enzymes, which are often involved in the pathogenesis of human diseases.T large number of worldwide spread diseases, affecting humans, insects and plants [31,[56][57][58], with a great impact on human health. In addition, infectious diseases strongly affect the world economy in terms of costs for the human health as well as food and agricultural economic losses [59]. The use of antibiotics to counteract the pathogen infections has represented the therapeutic strategy of choice in the last century, however the emergence of antibiotic resistance strains represents the major challenge of the 21st century [60][61][62]. Targeting bacterial pathogenic mechanisms by disarming pathogens of virulence factors, for instance by inhibiting the enzymatic activity of bART, represents a valid alternative intervention strategy to overcome antibiotic resistance [63][64][65][66]. In addition, because of the conservation of ADPr systems throughout the evolution, the understanding of bacterial pathogenic mechanisms may contribute to unveil novel and conserved cellular processes regulated by ADPr in high organisms [34,45,67,68]. The dysregulation of such processes can be either cause of human diseases or be target of therapeutic intervention [39,[69][70][71].Herein, we will provide a summary of bacterial ADPr systems describing their pathogenic mechanisms and highlighting the similarities with ADPr systems in mammals as well. Further, we discuss the potential of targeting ADPr for therapeutic strategies of infection diseases. ADP-ribosylation in pathophysiologyADPr was originally described in the 60s; two independent studies reported the identification of a new polymer, poly(ADP-ribose) (PAR) synthesised from NAD + in vertebrate cells [72] and, simultaneously, the finding that bacterial DTX activity from C. diphteriae is dependent on NAD + content [73]. In the following decades, research in the field has expanded the involvement of ADPr ...

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The coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression

Cited by 179 publications

References 82 publications

Both ADP-Ribosyl-Binding and Hydrolase Activities of the Alphavirus nsP3 Macrodomain Affect Neurovirulence in Mice

Both ADP-Ribosyl-Binding and Hydrolase Activities of the Alphavirus nsP3 Macrodomain Affect Neurovirulence in Mice

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

Targeting ADP-ribosylation as an antimicrobial strategy

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