2. Academic Validation
  3. PARP14 and PARP9/DTX3L regulate interferon-induced ADP-ribosylation

PARP14 and PARP9/DTX3L regulate interferon-induced ADP-ribosylation

  • EMBO J. 2024 Jun 4. doi: 10.1038/s44318-024-00126-0.
Pulak Kar # 1 2,  Chatrin Chatrin # 1,  Nina Đukić # 1,  Osamu Suyari 1,  Marion Schuller 1,  Kang Zhu 1,  Evgeniia Prokhorova 1,  Nicolas Bigot 3,  Juraj Ahel 4,  Jonas Damgaard Elsborg 5,  Michael L Nielsen 5,  Tim Clausen 4 6,  Sébastien Huet 3,  Mario Niepel 7,  Sumana Sanyal 1,  Dragana Ahel 1,  Rebecca Smith 8,  Ivan Ahel 9
Affiliations

Affiliations

  • 1 Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK.
  • 2 Department of Biological Sciences, SRM University-AP, Amaravati, 522502, India.
  • 3 Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, BIOSIT - UMS3480, F-35000, Rennes, France.
  • 4 Research Institute of Molecular Pathology (IMP), Vienna BioCenter, Vienna, Austria.
  • 5 Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
  • 6 Medical University of Vienna, Vienna, Austria.
  • 7 Ribon Therapeutics, Cambridge, MA, 02140, USA.
  • 8 Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK. rebecca.smith@path.ox.ac.uk.
  • 9 Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK. ivan.ahel@path.ox.ac.uk.
  • # Contributed equally.
PMID: 38834853 DOI: 10.1038/s44318-024-00126-0
Abstract

PARP-catalysed ADP-ribosylation (ADPr) is important in regulating various cellular pathways. Until recently, PARP-dependent mono-ADP-ribosylation has been poorly understood due to the lack of sensitive detection methods. Here, we utilised an improved antibody to detect mono-ADP-ribosylation. We visualised endogenous interferon (IFN)-induced ADP-ribosylation and show that PARP14 is a major Enzyme responsible for this modification. Fittingly, this signalling is reversed by the macrodomain from SARS-CoV-2 (Mac1), providing a possible mechanism by which Mac1 counteracts the activity of Antiviral PARPs. Our data also elucidate a major role of PARP9 and its binding partner, the E3 ubiquitin Ligase DTX3L, in regulating PARP14 activity through protein-protein interactions and by the hydrolytic activity of PARP9 macrodomain 1. Finally, we also present the first visualisation of ADPr-dependent ubiquitylation in the IFN response. These approaches should further advance our understanding of IFN-induced ADPr and ubiquitin signalling processes and could shed light on how different pathogens avoid such defence pathways.

Keywords

ADP-ribosylation; Immune Response; Interferon Response; SARS-CoV2; Ubiquitin.

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