PMID- 37695054
OWN - NLM
STAT- MEDLINE
DCOM- 20231005
LR  - 20240210
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 97
IP  - 9
DP  - 2023 Sep 28
TI  - PARP12 is required to repress the replication of a Mac1 mutant coronavirus in a 
      cell- and tissue-specific manner.
PG  - e0088523
LID - 10.1128/jvi.00885-23 [doi]
LID - e00885-23
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 murine hepatitis virus (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 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. 
      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, 
      USA.
FAU - Parthasarathy, Srivatsan
AU  - Parthasarathy S
AD  - Department of Molecular Biosciences, University of Kansas , Lawrence, Kansas, 
      USA.
FAU - Schwarting, Nancy
AU  - Schwarting N
AD  - Department of Molecular Biosciences, University of Kansas , Lawrence, Kansas, 
      USA.
FAU - O'Connor, Joseph J
AU  - O'Connor JJ
AD  - Department of Molecular Biosciences, University of Kansas , Lawrence, Kansas, 
      USA.
FAU - Pfannenstiel, Jessica J
AU  - Pfannenstiel JJ
AD  - Department of Molecular Biosciences, University of Kansas , Lawrence, Kansas, 
      USA.
FAU - Giri, Emily
AU  - Giri E
AD  - Department of Molecular Biosciences, University of Kansas , Lawrence, Kansas, 
      USA.
FAU - More, Sunil
AU  - More S
AD  - Department of Veterinary Pathology, Oklahoma State University , Stillwater, 
      Oklahoma, USA.
FAU - Orozco, Robin C
AU  - Orozco RC
AD  - Department of Molecular Biosciences, University of Kansas , Lawrence, Kansas, 
      USA.
FAU - Fehr, Anthony R
AU  - Fehr AR
AUID- ORCID: 0000-0003-1560-1573
AD  - Department of Molecular Biosciences, University of Kansas , Lawrence, Kansas, 
      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  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230911
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 9008-11-1 (Interferons)
RN  - EC 2.4.2.30 (PARP12 protein, mouse)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
SB  - IM
UOF - bioRxiv. 2023 Jun 17;:. PMID: 37398292
MH  - Animals
MH  - Mice
MH  - Coronavirus Infections/virology
MH  - Disease Models, Animal
MH  - *Genes, Viral
MH  - Interferons/immunology
MH  - Mice, Knockout
MH  - *Murine hepatitis virus/genetics/growth & development/metabolism/pathogenicity
MH  - *Mutation
MH  - Organ Specificity
MH  - *Poly(ADP-ribose) Polymerases/deficiency/genetics/metabolism
MH  - *Virus Replication/genetics
MH  - Cell Line
PMC - PMC10537751
OTO - NOTNLM
OT  - ADP-ribosylation
OT  - MHV
OT  - PARP
OT  - coronavirus
OT  - macrodomain
OT  - pathology
COIS- Anthony R. Fehr was named as an inventor on a patent filed by the University of 
      Kansas.
EDAT- 2023/09/11 12:43
MHDA- 2023/10/04 06:43
PMCR- 2023/09/28
CRDT- 2023/09/11 09:03
PHST- 2023/10/04 06:43 [medline]
PHST- 2023/09/11 12:43 [pubmed]
PHST- 2023/09/11 09:03 [entrez]
PHST- 2023/09/28 00:00 [pmc-release]
AID - 00885-23 [pii]
AID - jvi.00885-23 [pii]
AID - 10.1128/jvi.00885-23 [doi]
PST - ppublish
SO  - J Virol. 2023 Sep 28;97(9):e0088523. doi: 10.1128/jvi.00885-23. Epub 2023 Sep 11.