PARP PARG Macrodomain Viral Evasion Module

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

5 shared nodes are defined in this module.

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Cell Types

No cell types are annotated for this module.

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Biological Processes

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.

Discussions and Knowledge Gaps

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

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.

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Pathophysiology

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 innate immune response GO:0045087 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 INCREASED negative regulation of viral genome replication GO:0045071 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 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 DECREASED negative regulation of viral genome replication GO:0045071 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 INCREASED viral process GO:0016032 INCREASED

Used by disorders

COVID-19 as Enhanced Viral Replication and Tissue Pathology