PARP14 is a PARP with both ADP-ribosyl transferase and hydrolase activities

Sci Adv. 2023 Sep 15;9(37):eadi2687. doi: 10.1126/sciadv.adi2687.

Nina Đukić ¹, Øyvind Strømland ¹ ², Jonas Damgaard Elsborg ³, Deeksha Munnur ¹, Kang Zhu ¹, Marion Schuller ¹, Chatrin Chatrin ¹, Pulak Kar ¹, Lena Duma ¹, Osamu Suyari ¹, Johannes Gregor Matthias Rack ¹ ⁴, Domagoj Baretić ¹, Dorian Richard Kenneth Crudgington ¹, Joséphine Groslambert ¹, Gerissa Fowler ⁵, Sven Wijngaarden ⁶, Evgeniia Prokhorova ¹, Jan Rehwinkel ⁵, Herwig Schüler ⁷, Dmitri V Filippov ⁶, Sumana Sanyal ¹, Dragana Ahel ¹, Michael L Nielsen ³, Rebecca Smith ¹, Ivan Ahel ¹

Affiliations

1 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
2 Department of Biomedicine, University of Bergen, 5020 Bergen, Norway.
3 Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
4 MRC Centre for Medical Mycology, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK.
5 Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
6 Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, Netherlands.
7 Center for Molecular Protein Science, Department of Chemistry, Lund University, 22100 Lund, Sweden.

PMID: 37703374 DOI: 10.1126/sciadv.adi2687

Abstract

PARP14 is a mono-ADP-ribosyl transferase involved in the control of immunity, transcription, and DNA replication stress management. However, little is known about the ADP-ribosylation activity of PARP14, including its substrate specificity or how PARP14-dependent ADP-ribosylation is reversed. We show that PARP14 is a dual-function enzyme with both ADP-ribosyl transferase and hydrolase activity acting on both protein and nucleic acid substrates. In particular, we show that the PARP14 macrodomain 1 is an active ADP-ribosyl hydrolase. We also demonstrate hydrolytic activity for the first macrodomain of PARP9. We reveal that expression of a PARP14 mutant with the inactivated macrodomain 1 results in a marked increase in mono(ADP-ribosyl)ation of proteins in human cells, including PARP14 itself and Antiviral PARP13, and displays specific cellular phenotypes. Moreover, we demonstrate that the closely related hydrolytically active macrodomain of SARS2 Nsp3, Mac1, efficiently reverses PARP14 ADP-ribosylation in vitro and in cells, supporting the evolution of viral macrodomains to counteract PARP14-mediated Antiviral response.

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