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
  • 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. [email protected].
  • 9. Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK. [email protected].
  • # 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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