Macrodomain ADP-ribosylhydrolase and the pathogenesis of infectious diseases

Leung, Anthony K.L.; McPherson, Robert Lyle; Griffin, Diane E.

doi:10.1371/journal.ppat.1006864

Cited by 51 publications

(81 citation statements)

References 53 publications

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“…Viral nsP3 MDs have mono ADPr hydrolase as well as binding activity (27,49,50,75), and mutations that affect these functions of alphavirus nsP3 MDs attenuate virus replication and reduce neurovirulence in mice (27,31). Because several enzymatically active PARPs have demonstrated antiviral activity, are induced by IFN, and are under diversifying selective pressure (59)(60)(61)(62)(63)65), the MD and particularly its hydrolase function have been postulated to function primarily by countering the antiviral effects of ADP-ribosylated cellular proteins (64,65,75). Here, we show that ADP ribosylation is induced by alphavirus infection of neural cells independent of IFN production, that MARylation of cellular proteins promotes virus replication, and that nsP3 ADPr-binding and hydrolase activities are important for different aspects of virus replication.…”

Section: Discussionmentioning

confidence: 99%

“…However, the requirement for interaction with MARylated cellular proteins and the step(s) in replication affected by the loss of ADPr binding or hydrolase activity are not known. Because several PARPs can be induced by IFN, are under diversifying selection, and have antiviral activity, it has been postulated that the nsP3 MD is important for countering the antiviral activities of host proteins ADP-ribosylated by antiviral PARPs (59)(60)(61)(62)(63)(64)(65). In the present study, we determined that nsP3 MD -mediated ADPr binding is critical for establishing replication complexes to initiate infection and that hydrolase activity facilitates replication-complex amplification in infected neuronal cells; these observations are consistent with the high conservation of this region and its importance for neurovirulence.…”

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confidence: 99%

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ADP-ribosyl–binding and hydrolase activities of the alphavirus nsP3 macrodomain are critical for initiation of virus replication

Abraham

Hauer

McPherson

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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108

139

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Alphaviruses are plus-strand RNA viruses that cause encephalitis, rash, and arthritis. The nonstructural protein (nsP) precursor polyprotein is translated from genomic RNA and processed into four nsPs. nsP3 has a highly conserved macrodomain (MD) that binds ADP-ribose (ADPr), which can be conjugated to protein as a posttranslational modification involving transfer of ADPr from NAD + by poly ADPr polymerases (PARPs). The nsP3 MD also removes ADPr from mono ADP-ribosylated (MARylated) substrates. To determine which aspects of alphavirus replication require nsP3 MD ADPr-binding and/or hydrolysis function, we studied NSC34 neuronal cells infected with chikungunya virus (CHIKV). Infection induced ADP-ribosylation of cellular proteins without increasing PARP expression, and inhibition of MARylation decreased virus replication. CHIKV with a G32S mutation that reduced ADPr-binding and hydrolase activities was less efficient than WT CHIKV in establishing infection and in producing nsPs, dsRNA, viral RNA, and infectious virus. CHIKV with a Y114A mutation that increased ADPr binding but reduced hydrolase activity, established infection like WT CHIKV, rapidly induced nsP translation, and shut off host protein synthesis with reduced amplification of dsRNA. To assess replicase function independent of virus infection, a transreplicase system was used. Mutant nsP3 MD s D10A, G32E, and G112E with no binding or hydrolase activity had no replicase activity, G32S had little, and Y114A was intermediate to WT. Therefore, ADP ribosylation of proteins and nsP3 MD ADPr binding are necessary for initiation of alphavirus replication, while hydrolase activity facilitates amplification of replication complexes. These observations are consistent with observed nsP3 MD conservation and limited tolerance for mutation. alphavirus | macrodomain | ADP ribosylation | replication complexes | PARP

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

ADP-ribosyl–binding and hydrolase activities of the alphavirus nsP3 macrodomain are critical for initiation of virus replication

Abraham

Hauer

McPherson

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

108

139

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“…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%

“…Viral MDs are of the Macro D subclass that also has ADPribosylhydrolase activity and therefore can remove ADP-ribosylation from modified proteins (26,(41)(42)(43)(44)(45). Because several PARPs are regulated by interferon (IFN), have antiviral properties, and are under evolutionary diversifying selection (46)(47)(48)(49), it has been postulated that the primary function of viral MDs is to counter the host response to infection by removing ADPr from modified host proteins (50,51). However, chikungunya virus (CHIKV) with nsP3 MD mutations resulting in little or no hydrolase or binding activity is not viable in either mammalian or insect cells, indicating an important role for the alphavirus MD in virus replication (43).…”

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confidence: 99%

“…N24 is within the hydrolase loop and coordinates binding to the distal ribose, as does Y114. G32 is also in the hydrolase loop, and previous studies showed that amino acid substitutions at the equivalent of this position can fine-tune hydrolase activity (27,41,43,44,50,57). Purified wild-type (WT) and recombinant nsP3 MD mutant N24A, G32S, G32A, G32E, Y114A, and G32E/I113R/Y114N (triple-mutant [TM]) strains were assessed for MAR hydrolase activity ( Fig.…”

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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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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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Macrodomain ADP-ribosylhydrolase and the pathogenesis of infectious diseases

Cited by 51 publications

References 53 publications

ADP-ribosyl–binding and hydrolase activities of the alphavirus nsP3 macrodomain are critical for initiation of virus replication

ADP-ribosyl–binding and hydrolase activities of the alphavirus nsP3 macrodomain are critical for initiation of virus replication

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

Targeting ADP-ribosylation as an antimicrobial strategy

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