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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

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No cell types are annotated for this module.
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Biological Processes

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defense response to virus GO:0051607 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. INCREASED innate immune response GO:0045087 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. INCREASED protein poly-ADP-ribosylation GO:0070212 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. INCREASED negative regulation of viral genome replication GO:0045071 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. INCREASED protein poly-ADP-ribosylation GO:0070212 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. DECREASED negative regulation of viral genome replication GO:0045071 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. DECREASED viral genome replication GO:0019079 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. INCREASED viral process GO:0016032 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. INCREASED
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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 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. INCREASED innate immune response GO:0045087 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. INCREASED
Used by disorders
COVID-19
Downstream
  • NAD-Dependent Antiviral ADP-Ribosylation Induced PARP enzymes use NAD to write ADP-ribose marks on target proteins.
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 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. INCREASED negative regulation of viral genome replication GO:0045071 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. INCREASED
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.
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 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. DECREASED
Downstream
  • Viral Macrodomain De-ADP-Ribosylation Countermeasure Viral macrodomains mimic or compete with host erasure logic to oppose antiviral PARP-written marks.
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 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. DECREASED negative regulation of viral genome replication GO:0045071 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. DECREASED
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.
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 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. INCREASED viral process GO:0016032 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. INCREASED
Used by disorders
COVID-19 as Enhanced Viral Replication and Tissue Pathology