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Published on: September 5, 2016
PARP14 is an interferon (IFN)-induced host factor that promotes IFN production and affects the replication of
Srivatsan Parthasarathy1, Pradtahna Saenjamsai1, Hongping Hao1
1Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045, USA.
Abstract:
PARP14 is a 203 kDa multi-domain protein that is primarily known as an ADP-ribosyltransferase, and is involved in a variety of cellular functions including DNA damage, microglial activation, inflammation, and cancer progression. In addition, PARP14 is upregulated by interferon (IFN), indicating a role in the antiviral response. Furthermore, PARP14 has evolved under positive selection, again indicating that it is involved in host-pathogen conflict. We found that PARP14 is required for increased IFN-I production in response to coronavirus infection lacking ADP-ribosylhydrolase (ARH) activity and poly(I:C), however, whether it has direct antiviral function remains unclear. Here we demonstrate that the catalytic activity of PARP14 enhances IFN-β and IFN-λ responses and restricts ARH-deficient murine hepatitis virus (MHV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. To determine if PARP14's antiviral functions extended beyond CoVs, we tested the ability of herpes simplex virus 1 (HSV-1), a DNA virus, vesicular stomatitis virus (VSV), a negative-sense RNA virus, and lymphocytic choriomeningitis virus (LCMV), an ambisense RNA virus, to infect A549 PARP14 knockout (KO) cells. While LCMV infection was unaffected, HSV-1 replication was increased in PARP14 KO cells and VSV replication was decreased. These results indicate that PARP14 restricts HSV-1 replication but enhances the replication of VSV. A PARP14 active site inhibitor had no impact on HSV-1 or VSV replication, indicating that its effect on these viruses was independent of its catalytic activity. These data demonstrate that PARP14 promotes IFN production and has both proviral and antiviral functions targeting multiple viruses.
Insights
Poly(ADP-ribose) polymerase 14 (PARP14) enhances interferon production and restricts viral replication, exhibiting both pro- and antiviral functions against diverse viruses like coronaviruses and herpes simplex virus 1.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Poly(ADP-ribose) polymerase 14 (PARP14) is known for its roles in DNA damage, inflammation, and cancer.
- PARP14 is upregulated by interferon (IFN) and implicated in host-pathogen interactions.
- Previous studies suggested PARP14's involvement in IFN-I production during coronavirus infection but its direct antiviral role was unclear.
Purpose of the Study:
- To investigate the direct antiviral functions of PARP14.
- To determine if PARP14's catalytic activity is essential for its antiviral effects.
- To assess PARP14's impact on a broad range of viruses beyond coronaviruses.
Main Methods:
- Utilized PARP14 knockout (KO) A549 cells to study viral replication.
- Infected KO cells with various viruses, including murine hepatitis virus (MHV), SARS-CoV-2, herpes simplex virus 1 (HSV-1), vesicular stomatitis virus (VSV), Ebola virus (EBOV), and Nipah virus (NiV).
- Administered a PARP14 active site inhibitor to assess the role of catalytic activity.
Main Results:
- PARP14 catalytic activity enhanced IFN-I and IFN-III responses.
- PARP14 restricted replication of ARH-deficient MHV and SARS-CoV-2.
- PARP14 restricted HSV-1 replication, but was critical for efficient infection by VSV, EBOV, and NiV.
- PARP14's antiviral effects on HSV-1 and EBOV were independent of its catalytic activity.
Conclusions:
- PARP14 promotes interferon production, contributing to antiviral defense.
- PARP14 exhibits context-dependent antiviral functions, restricting some viruses while promoting others.
- PARP14 plays a multifaceted role in the host response to viral infections, impacting multiple virus families.
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