How host-cell enzymes combat the coronavirus

May 16, 2019

Host-cell enzymes called PARP12 and PARP14 are important for inhibiting mutant forms of a coronavirus, according to a study published May 16 in the open-access journal PLOS Pathogens by Stanley Perlman of the University of Iowa, Anthony Fehr of the University of Kansas, and colleagues.

A biochemical process called ADP-ribosylation facilitates the host response to virus infection. This process is catalyzed by enzymes called poly(ADP-ribose) polymerases (PARPs). Several viruses, including all members of the coronavirus family, which cause severe disease in agriculturally important and companion animals as well as humans, encode a macrodomain to reverse ADP-ribosylation and combat this immune response, facilitating viral replication and virulence. As such, viruses with mutations in the macrodomain are highly attenuated and cause minimal disease in organisms. These results suggest that macrodomains counter cellular ADP-ribosylation, but the potential role of PARPs in this process has not been clear.

In the new study, the authors used macrophage cells and mice infected with a coronavirus to identify PARPs, specifically PARP12 and PARP14, as host-cell ADP-ribosylating enzymes important for the attenuation of macrodomain-mutant viruses. The findings showed that the macrodomain is required to prevent PARP-mediated inhibition of coronavirus replication, and enhancement of the production of antiviral proteins called interferons. According to the authors, the results demonstrate a broad strategy of virus-host interactions, unveil previously unknown mechanisms of immune regulation, and indicate that the macrodomain may be a useful target for antiviral therapy.

The authors add, "ADP-ribosylation has increasingly been recognized as a host cell strategy to combat virus infections and viruses have learned how to counter this modification. Here we describe a previously unidentified interaction between the specific host cell enzymes that effect ADP-riboslylation and a viral protein that evades this host response."
Research Article

Funding: This study was supported in part by grants from the NIH (PO1 AI060699 (S.P.), RO1 AI091322 (S.P.), F32-AI113973 (A.R.F.), CoBRE P20 GM113117-02 (A.R.F.), K22 AI134993 (A.R.F.), R01 AI123231 (C.S.S.), and RO1 HL126901 (M.A.)), the Kowa Company, Ltd., Nagoya, Japan (M.A.), the McDaniel College Student-Faculty Research Fund (D.F.), the Jean Richards Chemistry Endowment (D.F.), and the University of Kansas (A.R.F.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

Citation: Grunewald ME, Chen Y, Kuny C, Maejima T, Lease R, Ferraris D, et al. (2019) The coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression. PLoS Pathog 15 (5): e1007756. ppat.1007756

Author Affiliations:

Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, United States of America

Department of Molecular Biosciences, University of Texas, Austin, TX, United States of America

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America

McDaniel College, Westminster, MD, United States of America

Department of Molecular Biosciences, University of Kansas, Lawrence, KS, United States of America

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