Coronavirus Infection and PARP Expression Dysregulate the NAD Metabolome: A Potentially Actionable Component of Innate Immunity

Collin D. Heer; Daniel J. Sanderson; Yousef M.O. Alhammad; Mark S. Schmidt; Samuel A.J. Trammell; Stanley Perlman; Michael S. Cohen; Anthony R. Fehr; Charles Brenner

Most CoV genomes encode 16 non-structural proteins (nsps) Zhu et al., 2020) . nsp3 contains a macrodomain, herein termed the CoV ADP-ribosylhydrolase (CARH), that removes monoADP-ribose modifications from acidic amino acids on protein targets. Thus, CARH reverses the modification that is installed by the IFN-induced activities of MARylating PARP family members (Fehr et al., 2016) . CARH activity is required for virulence in vivo using mouse models of both MHV and SARS-CoV (Eriksson, Cervantes-Barragan, Ludewig, & Thiel, 2008; Fehr et al., 2016) . Moreover, an active site mutation that ablates the ADP-ribosylhydrolase activity of CARH resulted in a virus that replicates poorly in primary bone-marrow derived macrophages (BMDMs) (Grunewald et al., 2019) . We further identified PARP12 and PARP14 as CoVinduced ISGs that are required for the depressed replication of CARH mutant viruses, indicating that their activity is opposed by CARH-mediated reversal of ADPribosylation (Grunewald et al., 2019) .