Global remodeling of ADP-ribosylation by PARP1 suppresses influenza A virus infection DOI Creative Commons
Zhenyu Zhang, Isabel Uribe,

Kaitlin A. Davis

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 19, 2024

SUMMARY ADP-ribosylation is a highly dynamic and fully reversible post-translational modification performed by poly(ADP-ribose) polymerases (PARPs) that modulates protein function, abundance, localization turnover. Here we show influenza A virus infection causes rapid dramatic upregulation of global inhibits viral replication. Mass spectrometry defined for the first time ADP-ribosylome during infection, creating an infection-specific profile with almost 4,300 sites on ∼1,080 host proteins, as well over 100 proteins. Our data indicate increase likely reflects change in form rather than new targets. Functional assays demonstrated replication machinery antagonizes its activity further revealed anti-viral PARPs counteracted NS1, assigning to primary antagonist innate immunity. We identified PARP1 enzyme producing majority present infection. Influenza replicated faster cells lacking PARP1, linking phenotype. Together, these establish immune-like response antagonized previously unknown NS1.

Language: Английский

The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2 DOI Creative Commons
Rahul K. Suryawanshi,

Priyadarshini Jaishankar,

G.J. Correy

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 9, 2024

SARS-CoV-2 continues to pose a threat public health. Current therapeutics remain limited direct acting antivirals that lack distinct mechanisms of action and are already showing signs viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) plays important role in the coronaviral lifecycle by suppressing host innate immune responses. Genetic inactivation Mac1 abrogates replication

Language: Английский

Citations

5
IFN-γ signaling is required for the efficient replication of murine hepatitis virus (MHV) strain JHM in the brains of infected mice. DOI Creative Commons
Catherine M. Kerr,

Macie A. Proctor-Roser,

Srivatsan Parthasarathy

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

ABSTRACT Neurotropic viruses are a major public health concern as they can cause encephalitis and other severe brain diseases. Many of these viruses, including flaviviruses, herpesviruses, rhabdoviruses alphaviruses enter the through olfactory neuroepithelium (ONE) in bulbs (OB). Due to low percentage that occurs following infections, it’s thought OBs have specialized innate immune responses eliminate viruses. Murine hepatitis virus strain JHM (JHMV) is model coronavirus causes mice access sensory neurons. We’ve shown JHMV Mac1-mutant virus, N1347A, has decreased replication disease brains mice. Here we further show this replicates poorly OB. However, it unknown which factors restrict N1347A RNA seq analysis infected showed IFNγ was upregulated OB while IFN- β barely detectable at 5 days post-infection. To determine if IFN-γ restricts replication, utilized receptor (IFN-γR) knockout (KO) Surprisingly found WT replicated very whole both IFN-γR KO intranasal infection, though survival weight loss were unaltered. Furthermore, determined microglia primary cells producing during early stages infection. We conclude required for efficient

Language: Английский

Citations

0
The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2 DOI Open Access
Rahul K. Suryawanshi,

Priyadarshini Jaishankar,

G.J. Correy

et al.

Published: Jan. 6, 2025

SARS-CoV-2 continues to pose a threat public health. Current therapeutics remain limited direct acting antivirals that lack distinct mechanisms of action and are already showing signs viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) plays important role in the coronaviral lifecycle by suppressing host innate immune responses. Genetic inactivation Mac1 abrogates replication vivo potentiating However, it is unknown whether this can be achieved pharmacologic inhibition therefore exploited therapeutically. Here we report potent selective lead small molecule, AVI-4206, effective model infection. Cellular models indicate AVI-4206 has high target engagement weakly inhibit gamma interferon- catalytic activity-dependent manner; stronger antiviral effect for observed human airway organoids. In animal severe infection, reduces replication, potentiates responses, leads survival benefit. Our results provide pharmacological proof concept valid therapeutic via novel immune-restoring mechanism could potentially synergize with existing therapies targeting distinct, essential aspects life cycle. This approach more widely used other macrodomains develop beyond COVID-19.

Language: Английский

Citations

0
The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2 DOI Open Access
Rahul K. Suryawanshi,

Priyadarshini Jaishankar,

G.J. Correy

et al.

Published: Jan. 6, 2025

SARS-CoV-2 continues to pose a threat public health. Current therapeutics remain limited direct acting antivirals that lack distinct mechanisms of action and are already showing signs viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) plays important role in the coronaviral lifecycle by suppressing host innate immune responses. Genetic inactivation Mac1 abrogates replication vivo potentiating However, it is unknown whether this can be achieved pharmacologic inhibition therefore exploited therapeutically. Here we report potent selective lead small molecule, AVI-4206, effective model infection. Cellular models indicate AVI-4206 has high target engagement weakly inhibit gamma interferon- catalytic activity-dependent manner; stronger antiviral effect for observed human airway organoids. In animal severe infection, reduces replication, potentiates responses, leads survival benefit. Our results provide pharmacological proof concept valid therapeutic via novel immune-restoring mechanism could potentially synergize with existing therapies targeting distinct, essential aspects life cycle. This approach more widely used other macrodomains develop beyond COVID-19.

Language: Английский

Citations

0
A multidomain PARP14 construct suitable for bacterial expression DOI Creative Commons
Constantinos Chatzicharalampous, H. Schüler

Protein Expression and Purification, Journal Year: 2024, Volume and Issue: 224, P. 106580 - 106580

Published: Aug. 17, 2024

Poly-ADP-ribose polymerase-14 (PARP14) can modify proteins and nucleic acids by the reversible addition of a single ADP-ribose molecule. Aberrant PARP14 functions have been related to cancer inflammation, its domains are involved in processes viral infection. Previous research indicates that might be mediated via multitude target proteins. In vitro studies this large multidomain enzyme complicated difficulties obtain biochemical quantities pure protein. Here we present strategy allows bacterial expression purification functional construct PARP14. We substituted an internal KH domain neighboring unstructured region with SUMO protein encompasses three macrodomains, WWE domain, PARP catalytic domain. show resulting retains both ADP-ribosyltransferase de-MARylase activities. This will useful structural

Language: Английский

Citations

0
Global remodeling of ADP-ribosylation by PARP1 suppresses influenza A virus infection DOI Creative Commons
Zhenyu Zhang, Isabel Uribe,

Kaitlin A. Davis

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 19, 2024

SUMMARY ADP-ribosylation is a highly dynamic and fully reversible post-translational modification performed by poly(ADP-ribose) polymerases (PARPs) that modulates protein function, abundance, localization turnover. Here we show influenza A virus infection causes rapid dramatic upregulation of global inhibits viral replication. Mass spectrometry defined for the first time ADP-ribosylome during infection, creating an infection-specific profile with almost 4,300 sites on ∼1,080 host proteins, as well over 100 proteins. Our data indicate increase likely reflects change in form rather than new targets. Functional assays demonstrated replication machinery antagonizes its activity further revealed anti-viral PARPs counteracted NS1, assigning to primary antagonist innate immunity. We identified PARP1 enzyme producing majority present infection. Influenza replicated faster cells lacking PARP1, linking phenotype. Together, these establish immune-like response antagonized previously unknown NS1.

Language: Английский

Citations

0