PMID- 37398292
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231106
DP  - 2023 Jun 17
TI  - PARP12 is required to repress the replication of a Mac1 mutant coronavirus in a 
      cell and tissue specific manner.
LID - 2023.06.16.545351 [pii]
LID - 10.1101/2023.06.16.545351 [doi]
AB  - ADP-ribosyltransferases (ARTs) mediate the transfer of ADP-ribose from NAD (+) to 
      protein or nucleic acid substrates. This modification can be removed by several 
      different types of proteins, including macrodomains. Several ARTs, also known as 
      PARPs, are stimulated by interferon, indicating ADP-ribosylation is an important 
      aspect of the innate immune response. All coronaviruses (CoVs) encode for a 
      highly conserved macrodomain (Mac1) that is critical for CoVs to replicate and 
      cause disease, indicating that ADP-ribosylation can effectively control 
      coronavirus infection. Our siRNA screen indicated that PARP12 might inhibit the 
      replication of a MHV Mac1 mutant virus in bone-marrow derived macrophages 
      (BMDMs). To conclusively demonstrate that PARP12 is a key mediator of the 
      antiviral response to CoVs both in cell culture and in vivo , we produced PARP12 
      (-/-) mice and tested the ability of MHV A59 (hepatotropic/neurotropic) and JHM 
      (neurotropic) Mac1 mutant viruses to replicate and cause disease in these mice. 
      Notably, in the absence of PARP12, Mac1 mutant replication was increased in BMDMs 
      and in mice. In addition, liver pathology was also increased in A59 infected 
      mice. However, the PARP12 knockout did not restore Mac1 mutant virus replication 
      to WT virus levels in all cell or tissue types and did not significantly increase 
      the lethality of Mac1 mutant viruses. These results demonstrate that while PARP12 
      inhibits MHV Mac1 mutant virus infection, additional PARPs or innate immune 
      factors must contribute to the extreme attenuation of this virus in mice. 
      IMPORTANCE: Over the last decade, the importance of ADP-ribosyltransferases 
      (ARTs), also known as PARPs, in the antiviral response has gained increased 
      significance as several were shown to either restrict virus replication or impact 
      innate immune responses. However, there are few studies showing ART-mediated 
      inhibition of virus replication or pathogenesis in animal models. We found that 
      the CoV macrodomain (Mac1) was required to prevent ART-mediated inhibition of 
      virus replication in cell culture. Here, using knockout mice, we found that 
      PARP12, an interferon-stimulated ART, was required to repress the replication of 
      a Mac1 mutant CoV both in cell culture and in mice, demonstrating that PARP12 
      represses coronavirus replication. However, the deletion of PARP12 did not fully 
      rescue Mac1 mutant virus replication or pathogenesis, indicating that multiple 
      PARPs function to counter coronavirus infection.
FAU - Kerr, Catherine M
AU  - Kerr CM
AD  - Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 
      66045, USA.
FAU - Parthasarathy, Srivatsan
AU  - Parthasarathy S
AD  - Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 
      66045, USA.
FAU - Schwarting, Nancy
AU  - Schwarting N
AD  - Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 
      66045, USA.
FAU - O'Connor, Joseph J
AU  - O'Connor JJ
AD  - Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 
      66045, USA.
FAU - Giri, Emily
AU  - Giri E
AD  - Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 
      66045, USA.
FAU - More, Sunil
AU  - More S
AD  - Department of Veterinary Pathology, Oklahoma State University, Stillwater 
      Oklahoma 74048, USA.
FAU - Orozco, Robin C
AU  - Orozco RC
AD  - Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 
      66045, USA.
FAU - Fehr, Anthony R
AU  - Fehr AR
AD  - Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 
      66045, USA.
LA  - eng
GR  - P20 GM113117/GM/NIGMS NIH HHS/United States
GR  - T32 GM132061/GM/NIGMS NIH HHS/United States
GR  - P30 CA168524/CA/NCI NIH HHS/United States
GR  - R35 GM138029/GM/NIGMS NIH HHS/United States
GR  - K22 AI134993/AI/NIAID NIH HHS/United States
PT  - Preprint
DEP - 20230617
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
UIN - J Virol. 2023 Sep 11;:e0088523. PMID: 37695054
PMC - PMC10312760
COIS- Competing interests: Anthony R. Fehr was named as an inventor on a patent filed 
      by the University of Kansas.
EDAT- 2023/07/03 13:06
MHDA- 2023/07/03 13:07
PMCR- 2023/06/30
CRDT- 2023/07/03 11:45
PHST- 2023/07/03 13:07 [medline]
PHST- 2023/07/03 13:06 [pubmed]
PHST- 2023/07/03 11:45 [entrez]
PHST- 2023/06/30 00:00 [pmc-release]
AID - 2023.06.16.545351 [pii]
AID - 10.1101/2023.06.16.545351 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Jun 17:2023.06.16.545351. doi: 
      10.1101/2023.06.16.545351.