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The coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression.
PLoS Pathog. 2019 05; 15(5):e1007756.PP

Abstract

ADP-ribosylation is a ubiquitous post-translational addition of either monomers or polymers of ADP-ribose to target proteins by ADP-ribosyltransferases, usually by interferon-inducible diphtheria toxin-like enzymes known as PARPs. While several PARPs have known antiviral activities, these activities are mostly independent of ADP-ribosylation. Consequently, less is known about the antiviral effects of ADP-ribosylation. Several viral families, including Coronaviridae, Togaviridae, and Hepeviridae, encode for macrodomain proteins that bind to and hydrolyze ADP-ribose from proteins and are critical for optimal replication and virulence. These results suggest that macrodomains counter cellular ADP-ribosylation, but whether PARPs or, alternatively, other ADP-ribosyltransferases cause this modification is not clear. Here we show that pan-PARP inhibition enhanced replication and inhibited interferon production in primary macrophages infected with macrodomain-mutant but not wild-type coronavirus. Specifically, knockdown of two abundantly expressed PARPs, PARP12 and PARP14, led to increased replication of mutant but did not significantly affect wild-type virus. PARP14 was also important for the induction of interferon in mouse and human cells, indicating a critical role for this PARP in the regulation of innate immunity. In summary, these data demonstrate that the macrodomain is required to prevent PARP-mediated inhibition of coronavirus replication and enhancement of interferon production.

Authors+Show 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.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.McDaniel College, Westminster, MD, 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.Department of Molecular Biosciences, University of Texas, Austin, TX, United States of America.Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, United States of America.Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, United States of America. Department of Molecular Biosciences, University of Kansas, Lawrence, KS, United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31095648

Citation

Grunewald, Matthew E., et al. "The Coronavirus Macrodomain Is Required to Prevent PARP-mediated Inhibition of Virus Replication and Enhancement of IFN Expression." PLoS Pathogens, vol. 15, no. 5, 2019, pp. e1007756.
Grunewald ME, Chen Y, Kuny C, et al. The coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression. PLoS Pathog. 2019;15(5):e1007756.
Grunewald, M. E., Chen, Y., Kuny, C., Maejima, T., Lease, R., Ferraris, D., Aikawa, M., Sullivan, C. S., Perlman, S., & Fehr, A. R. (2019). The coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression. PLoS Pathogens, 15(5), e1007756. https://doi.org/10.1371/journal.ppat.1007756
Grunewald ME, et al. The Coronavirus Macrodomain Is Required to Prevent PARP-mediated Inhibition of Virus Replication and Enhancement of IFN Expression. PLoS Pathog. 2019;15(5):e1007756. PubMed PMID: 31095648.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression. AU - Grunewald,Matthew E, AU - Chen,Yating, AU - Kuny,Chad, AU - Maejima,Takashi, AU - Lease,Robert, AU - Ferraris,Dana, AU - Aikawa,Masanori, AU - Sullivan,Christopher S, AU - Perlman,Stanley, AU - Fehr,Anthony R, Y1 - 2019/05/16/ PY - 2019/01/25/received PY - 2019/04/09/accepted PY - 2019/5/17/entrez PY - 2019/5/17/pubmed PY - 2019/11/19/medline SP - e1007756 EP - e1007756 JF - PLoS pathogens JO - PLoS Pathog. VL - 15 IS - 5 N2 - ADP-ribosylation is a ubiquitous post-translational addition of either monomers or polymers of ADP-ribose to target proteins by ADP-ribosyltransferases, usually by interferon-inducible diphtheria toxin-like enzymes known as PARPs. While several PARPs have known antiviral activities, these activities are mostly independent of ADP-ribosylation. Consequently, less is known about the antiviral effects of ADP-ribosylation. Several viral families, including Coronaviridae, Togaviridae, and Hepeviridae, encode for macrodomain proteins that bind to and hydrolyze ADP-ribose from proteins and are critical for optimal replication and virulence. These results suggest that macrodomains counter cellular ADP-ribosylation, but whether PARPs or, alternatively, other ADP-ribosyltransferases cause this modification is not clear. Here we show that pan-PARP inhibition enhanced replication and inhibited interferon production in primary macrophages infected with macrodomain-mutant but not wild-type coronavirus. Specifically, knockdown of two abundantly expressed PARPs, PARP12 and PARP14, led to increased replication of mutant but did not significantly affect wild-type virus. PARP14 was also important for the induction of interferon in mouse and human cells, indicating a critical role for this PARP in the regulation of innate immunity. In summary, these data demonstrate that the macrodomain is required to prevent PARP-mediated inhibition of coronavirus replication and enhancement of interferon production. SN - 1553-7374 UR - https://www.unboundmedicine.com/medline/citation/31095648/The_coronavirus_macrodomain_is_required_to_prevent_PARP_mediated_inhibition_of_virus_replication_and_enhancement_of_IFN_expression_ L2 - http://dx.plos.org/10.1371/journal.ppat.1007756 DB - PRIME DP - Unbound Medicine ER -