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PARP14 is regulated by the PARP9/DTX3L complex and promotes interferon γ-induced ADP-ribosylation

Victoria Chaves Ribeiro1, Lilian Cristina Russo1, Nícolas Carlos Hoch2

  • 1Department of Biochemistry, University of São Paulo, São Paulo, 05508-000, Brazil.

The EMBO Journal
|June 4, 2024
PubMed

Insights

Host ADP-ribosylation, crucial for antiviral defense, is mediated by PARP14 and the PARP9/DTX3L complex. SARS-CoV-2 Nsp3 counteracts this host response by hydrolyzing ADP-ribosylation modifications.

Area of Science:

  • Molecular Biology
  • Immunology
  • Virology

Background:

  • Protein ADP-ribosylation is implicated in antiviral signaling, including interferon responses.
  • Viruses like coronaviruses possess hydrolases that reverse host ADP-ribosylation, suggesting its importance in host-pathogen interactions.
  • The specific host ADP-ribosyltransferases, their targets, and their impact on viral infection remain largely unknown.

Purpose of the Study:

  • To identify the host ADP-ribosyltransferases involved in antiviral signaling.
  • To elucidate the mechanisms by which these enzymes regulate host responses to viral infections.
  • To investigate the interaction between host ADP-ribosylation and viral counteracting mechanisms.

Main Methods:

  • Investigated interferon-gamma (IFNγ) induced ADP-ribosyltransferase activity.
  • Analyzed the roles of PARP14, PARP9, and DTX3L in regulating protein levels and localization.
  • Examined the localization of these complexes in IFNγ-induced cytoplasmic inclusions.
  • Assessed the hydrolytic activity of SARS-CoV-2 Nsp3 macrodomain on ADP-ribosylated proteins.

Main Results:

  • Host ADP-ribosylation activity induced by IFNγ relies on PARP14 catalytic activity.
  • The PARP9/DTX3L complex maintains PARP14 protein levels through post-translational modifications.
  • PARP14, PARP9/DTX3L, and ADP-ribosylated proteins co-localize in IFNγ-induced cytoplasmic inclusions.
  • PARP14 and DTX3L are substrates for PARP14-mediated ADP-ribosylation.
  • The SARS-CoV-2 Nsp3 macrodomain hydrolyzes these ADP-ribosylation modifications.

Conclusions:

  • The PARP9/DTX3L complex and PARP14 are key components of the host's IFNγ-induced antiviral ADP-ribosylation response.
  • SARS-CoV-2 Nsp3 antagonizes host antiviral defenses by removing critical ADP-ribosylation marks.
  • This study reveals a complex interplay between host ADP-ribosyltransferases and viral counter-mechanisms.
Keywords:
ADP-RibosylationCoronavirusInnate ImmunityInterferonPARP

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