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PARP PARG Macrodomain Viral Evasion Module

Infectious disease Immunology Module parp_parg_macrodomain_viral_evasion 1 disorder Pathograph 5
A conserved RNA-virus host-response module centered on NAD-dependent ADP-ribosylation. Viral infection and interferon signaling induce noncanonical PARPs that MARylate or PARylate host and viral proteins, restricting viral replication, shaping stress granules, and promoting innate cytokine responses. PARG and host macrodomains reset ADP-ribose marks, while viral macrodomains encoded by coronaviruses, alphaviruses, hepeviruses, and related RNA viruses erase ADP-ribose modifications to counter host antiviral defenses and support replication or pathogenesis.
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Pathophysiology Nodes

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5 shared nodes are defined in this module.
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Cell Types

0
No cell types are annotated for this module.
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Biological Processes

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defense response to virus GO:0051607 ↑ INCREASED Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased defense response to virus (GO:0051607). GO:0051607 is a biological process from the Gene Ontology. innate immune response GO:0045087 ↑ INCREASED Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased innate immune response (GO:0045087). GO:0045087 is a biological process from the Gene Ontology. protein poly-ADP-ribosylation GO:0070212 ↑ INCREASED Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased protein poly-ADP-ribosylation (GO:0070212). GO:0070212 is a biological process from the Gene Ontology. negative regulation of viral genome replication GO:0045071 ↑ INCREASED Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased negative regulation of viral genome replication (GO:0045071). GO:0045071 is a biological process from the Gene Ontology. protein poly-ADP-ribosylation GO:0070212 ↓ DECREASED Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves decreased protein poly-ADP-ribosylation (GO:0070212). GO:0070212 is a biological process from the Gene Ontology. negative regulation of viral genome replication GO:0045071 ↓ DECREASED Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves decreased negative regulation of viral genome replication (GO:0045071). GO:0045071 is a biological process from the Gene Ontology. viral genome replication GO:0019079 ↑ INCREASED Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased viral genome replication (GO:0019079). GO:0019079 is a biological process from the Gene Ontology. viral process GO:0016032 ↑ INCREASED Gene Ontology (GO) Relation: this mechanism module involves this biological process This mechanism module involves increased viral process (GO:0016032). GO:0016032 is a biological process from the Gene Ontology.
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Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (for example, "parp_parg_macrodomain_viral_evasion#Viral Macrodomain De-ADP-Ribosylation Countermeasure"). The module is intended for RNA virus infections where PARP-dependent antiviral ADP-ribosylation, host NAD metabolism, PARG/PAR turnover, or viral macrodomain activity is a disease or therapeutic control point. SARS-CoV-2 Mac1, alphavirus nsP3 macrodomains, and HEV ORF1 macrodomains are exemplars rather than required disease-specific details.
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Mechanistic Hypotheses

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Canonical PARP Antiviral ADP-Ribosylation Model
canonical_parp_antiviral_adp_ribosylation_model CANONICAL Evidence: 1
Evidence balance 1 support
Interferon and viral infection induce noncanonical PARPs whose NAD-dependent ADP-ribosylation activity participates in host antiviral defense and limits viral replication.
Viral Macrodomain Countermeasure Model
viral_macrodomain_countermeasure_model CANONICAL Evidence: 1
Evidence balance 1 support
Viral macrodomains erase mono- or poly-ADP-ribose from proteins, opposing PARP-mediated antiviral defenses, stress-granule restriction, and cytokine responses.
PAR/PARG Turnover Balance Model
par_pool_balance_model EMERGING Evidence: 1
Evidence balance 1 support
The balance between PARP-written ADP-ribose marks and PARG or macrodomain erasure determines which antiviral, stress-granule, replication, or inflammatory outputs dominate in a given virus-cell context.
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Discussions and Knowledge Gaps

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Which ADP-ribosylated host or viral target proteins determine whether the PARP/PARG/macrodomain axis primarily controls viral RNA synthesis, stress-granule persistence, interferon output, or inflammatory pathology?
KNOWLEDGE GAP OPEN gap_adp_ribosylome_targets_in_viral_evasion
Attached to: NAD-Dependent Antiviral ADP-Ribosylation PARG and Host De-ADP-Ribosylation Reset Viral Macrodomain De-ADP-Ribosylation Countermeasure
The module captures the conserved causal pattern, but disease-specific entries will need target-level evidence to decide which ADP-ribosylated proteins are the actionable pivot points for a given virus and tissue.
Proposed experiments: Viral ADP-ribosylome macrodomain and PARG perturbation map
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Used By Disorder Entries

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COVID-19 via RNA Virus-Induced Interferon and PARP Activation , Host PARP9/DTX3L Antiviral ADP-Ribosylation → NAD-Dependent Antiviral ADP-Ribosylation , Nsp3 Macrodomain De-ADP-Ribosylation Countermeasure → Viral Macrodomain De-ADP-Ribosylation Countermeasure , Enhanced Viral Replication and Tissue Pathology → Enhanced Viral Replication and Pathogenesis
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.
Pathograph: causal mechanism network for PARP PARG Macrodomain Viral Evasion Module Interactive directed graph showing how this shared module's pathophysiology nodes connect.
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Pathophysiology

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RNA Virus-Induced Interferon and PARP Activation
trigger
RNA virus infection and interferon signaling induce noncanonical PARP enzymes, including PARP7/TIPARP, PARP10, PARP12, and PARP14 in coronavirus contexts. This creates an NAD-consuming antiviral enzyme state upstream of ADP-ribosylation-dependent host restriction.
defense response to virus GO:0051607 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased defense response to virus (GO:0051607). GO:0051607 is a biological process from the Gene Ontology. innate immune response GO:0045087 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased innate immune response (GO:0045087). GO:0045087 is a biological process from the Gene Ontology.
Used by disorders
COVID-19
Downstream
  • NAD-Dependent Antiviral ADP-Ribosylation Induced PARP enzymes use NAD to write ADP-ribose marks on target proteins.
Show evidence (2 references)
PMID:33051211 SUPPORT In Vitro
"Our data indicate that (i) CoV infection initiates the expression of multiple noncanonical PARP isozymes and dysregulates other genes involved in NAD metabolism, (ii) CoV infection and PARP10 expression can dramatically decrease NAD+ accumulation, and (iii) NAD+ boosting agents can improve PARP..."
SARS-CoV-2 infection data support virus-induced PARP and NAD-metabolism remodeling as the upstream state.
PMID:32244383 SUPPORT Other
"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."
Review evidence links interferon-induced PARPs to antiviral host defense.
NAD-Dependent Antiviral ADP-Ribosylation
central effector
PARP enzymes transfer ADP-ribose from NAD onto target proteins as mono- or poly-ADP-ribose marks. In infected cells, noncanonical PARP activity can restrict viral replication, promote interferon output, and alter stress granule biology.
protein poly-ADP-ribosylation GO:0070212 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased protein poly-ADP-ribosylation (GO:0070212). GO:0070212 is a biological process from the Gene Ontology. negative regulation of viral genome replication GO:0045071 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased negative regulation of viral genome replication (GO:0045071). GO:0045071 is a biological process from the Gene Ontology.
Used by disorders
COVID-19 as Host PARP9/DTX3L Antiviral ADP-Ribosylation
Downstream
  • PARG and Host De-ADP-Ribosylation Reset Host hydrolases can reverse ADP-ribose marks and reset the PAR/MAR state.
  • Viral Macrodomain De-ADP-Ribosylation Countermeasure Viral macrodomains oppose the same PARP-written antiviral marks.
Show evidence (2 references)
PMID:32244383 SUPPORT Other
"ADP-ribose is covalently attached to target proteins by poly-ADP-ribose polymerases (PARPs), using nicotinamide adenine dinucleotide (NAD+) as a substrate."
Defines the NAD-dependent PARP writing reaction that creates the antiviral ADP-ribosylation state.
PMID:33051211 SUPPORT In Vitro
"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."
Supports the dependence of antiviral PARP activity on NAD availability.
PARG and Host De-ADP-Ribosylation Reset
amplifier
PARG removes poly-ADP-ribose polymers, while host macrodomains remove selected mono-ADP-ribose marks. This host erasure layer controls the duration and amplitude of ADP-ribosylation signals and is a natural comparison point for viral macrodomain activity.
protein poly-ADP-ribosylation GO:0070212 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein poly-ADP-ribosylation (GO:0070212). GO:0070212 is a biological process from the Gene Ontology.
Downstream
  • Viral Macrodomain De-ADP-Ribosylation Countermeasure Viral macrodomains mimic or compete with host erasure logic to oppose antiviral PARP-written marks.
Show evidence (2 references)
PMID:32244383 SUPPORT Other
"ADP-ribosylation is a reversible modification via several enzymes that belong either to the ADP-ribosylglycohydrolase (DraG-like) family or to the macrodomain family [19]."
Supports ADP-ribosylation reversibility through host enzyme families.
PMID:32244383 SUPPORT Other
"Some of these enzymes hydrolyze a single unit of MAR, whereas the poly-ADP-ribose glycohydrolases (PARGs) can remove polymers of ADP-ribose molecules at O-glycosidic bonds [20,21,22,23]."
Directly supports PARG as the host enzyme class that removes poly-ADP-ribose polymers.
Viral Macrodomain De-ADP-Ribosylation Countermeasure
adaptive escape
Viral macrodomains bind and hydrolyze ADP-ribose modifications on host or viral proteins. By erasing PARP-written marks, they can blunt interferon production, disrupt antiviral stress granules, and remove restrictions on viral RNA synthesis or pathogenesis.
protein poly-ADP-ribosylation GO:0070212 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein poly-ADP-ribosylation (GO:0070212). GO:0070212 is a biological process from the Gene Ontology. negative regulation of viral genome replication GO:0045071 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of viral genome replication (GO:0045071). GO:0045071 is a biological process from the Gene Ontology.
Used by disorders
COVID-19 as Nsp3 Macrodomain De-ADP-Ribosylation Countermeasure
Downstream
  • Enhanced Viral Replication and Pathogenesis Viral de-ADP-ribosylation removes antiviral restrictions and can restore replication fitness or in vivo virulence.
Show evidence (3 references)
PMID:33158944 SUPPORT In Vitro
"Mac1 likely counters host-mediated antiviral ADP-ribosylation, a posttranslational modification that is part of the host response to viral infections."
SARS-CoV-2 Mac1 biochemical evidence supports viral macrodomain counteraction of host antiviral ADP-ribosylation.
PMID:27440879 SUPPORT In Vitro
"Here, we show that viral macro domains reverse cellular ADP-ribosylation, potentially cutting the signal of a viral infection in the cell."
Establishes viral macrodomains as ADP-ribosylation erasers that can blunt infection-associated signals.
PMID:32244383 SUPPORT Other
"Studies from the past 15 years have clearly shown that viral macrodomains bind MAR- and PARylated proteins and enzymatically hydrolyze ADP-ribose from proteins."
Review evidence supports both MAR/PAR binding and enzymatic erasure by viral macrodomains.
Enhanced Viral Replication and Pathogenesis
consequence
When viral macrodomains successfully counter antiviral ADP-ribosylation, viruses can improve RNA synthesis, productive infection, tissue replication, or pathogenesis. Conversely, catalytic macrodomain defects attenuate replication or virulence and nominate macrodomains as antiviral targets.
viral genome replication GO:0019079 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased viral genome replication (GO:0019079). GO:0019079 is a biological process from the Gene Ontology. viral process GO:0016032 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased viral process (GO:0016032). GO:0016032 is a biological process from the Gene Ontology.
Used by disorders
COVID-19 as Enhanced Viral Replication and Tissue Pathology
Show evidence (3 references)
PMID:35297669 SUPPORT In Vitro
"Our findings indicate that viral poly-ARH activity is uniquely required for high titer replication in mammalian systems."
Sindbis virus evidence directly links macrodomain poly-ADP-ribose hydrolase activity to high-titer replication.
PMID:35297669 SUPPORT In Vitro
"These domains erase mono- or poly-ADP-ribose, posttranslational modifications written by host poly-ADP-ribose polymerase (PARP) proteins, from undetermined host or viral proteins to enhance replication."
Supports the final causal edge from viral ADP-ribose erasure to enhanced replication.
PMID:33158944 SUPPORT Model Organism
"Mac1 is essential for pathogenesis in multiple animal models of CoV infection, implicating it as a virulence factor and potential therapeutic target."
Connects coronavirus macrodomain activity to pathogenesis and therapeutic targetability.