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

Protein ADP-ribosylation plays important but ill-defined roles in antiviral signalling cascades such as the interferon response. Several viruses of clinical interest, including coronaviruses, express hydrolases that reverse ADP-ribosylation catalysed by host enzymes, suggesting an important role for this modification in host-pathogen interactions. However, which ADP-ribosyltransferases mediate host ADP-ribosylation, what proteins ...
and pathways they target and how these modifications affect viral infection and pathogenesis is currently unclear. Here we show that host ADP-ribosyltransferase activity induced by IFN? signalling depends on PARP14 catalytic activity and that the PARP9/DTX3L complex is required to uphold PARP14 protein levels via post-translational mechanisms. Both the PARP9/DTX3L complex and PARP14 localise to IFN?-induced cytoplasmic inclusions containing ADP-ribosylated proteins, and both PARP14 itself and DTX3L are likely targets of PARP14 ADP-ribosylation. We provide evidence that these modifications are hydrolysed by the SARS-CoV-2 Nsp3 macrodomain, shedding light on the intricate cross-regulation between IFN-induced ADP-ribosyltransferases and the potential roles of the coronavirus macrodomain in counteracting their activity.
Mesh Terms:
ADP Ribose Transferases, ADP-Ribosylation, HEK293 Cells, Host-Pathogen Interactions, Humans, Interferon-gamma, Neoplasm Proteins, Poly(ADP-ribose) Polymerases, Protein Processing, Post-Translational, SARS-CoV-2, Ubiquitin-Protein Ligases
EMBO J
Date: Jul. 01, 2024
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