Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity

Collin D Heer; Daniel J Sanderson; Lynden S Voth; Yousef M.O Alhammad; Mark S Schmidt; Samuel A.J Trammell; Stanley Perlman; Michael S Cohen; Anthony R Fehr; Charles Brenner

doi:10.1074/jbc.RA120.015138

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Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity

Journal article

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Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity

Collin D Heer, Daniel J Sanderson, Lynden S Voth, Yousef M.O Alhammad, Mark S Schmidt, Samuel A.J Trammell, Stanley Perlman, Michael S Cohen, Anthony R Fehr and Charles Brenner

The Journal of biological chemistry, Vol.295(52), pp.17986-17996

12/25/2020

DOI: 10.1074/jbc.RA120.015138

PMID: 33051211

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Abstract

Poly(ADP-ribose) polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as the source of ADPR. Although the well-known poly(ADP-ribosylating) (PARylating) PARPs primarily function in the DNA damage response, many noncanonical mono(ADP-ribosylating) (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust up-regulation of several PARPs following infection with murine hepatitis virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly up-regulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while down-regulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD+ and NADP+. Finally, we show that NAMPT activation, NAM, and NR dramatically decrease the replication of an MHV that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses.

post-translational modification (PTM)

gene transcription

nicotinamide adenine dinucleotide (NAD)

poly(ADP-ribose) polymerase

PARP

interferon

Severe acute respiratory syndrome coronavirus 2

COVID-19

SARS-CoV-2

RNA-Seq

NAD biosynthesis

transcriptomics

plus-stranded RNA virus

ADP-ribosylation

Details

Title: Subtitle: Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity
Creators: Collin D Heer - Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, Iowa, USA
Daniel J Sanderson - Department of Chemical Physiology & Biochemistry, Oregon Health Sciences University, Portland, Oregon, USA
Lynden S Voth - Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA
Yousef M.O Alhammad - Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA
Mark S Schmidt - Department of Biochemistry, University of Iowa, Iowa City, Iowa, USA
Samuel A.J Trammell - Department of Biochemistry, University of Iowa, Iowa City, Iowa, USA
Stanley Perlman - Department of Microbiology & Immunology, University of Iowa, Iowa City, Iowa, USA
Michael S Cohen - Department of Chemical Physiology & Biochemistry, Oregon Health Sciences University, Portland, Oregon, USA
Anthony R Fehr - Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA
Charles Brenner - Department of Biochemistry, University of Iowa, Iowa City, Iowa, USA
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.295(52), pp.17986-17996
DOI: 10.1074/jbc.RA120.015138
PMID: 33051211
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/100000050, name: HHS | NIH | National Heart, Lung, and Blood Institute, award: HL147545; DOI: 10.13039/100000057, name: HHS | NIH | National Institute of General Medical Sciences, award: GM008629; DOI: 10.13039/100000057, name: HHS | NIH | National Institute of General Medical Sciences, award: GM113117; DOI: 10.13039/100006492, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: AI134993; DOI: 10.13039/100006492, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: AI060699; DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: AI091322; DOI: 10.13039/100000054, name: HHS | NIH | National Cancer Institute, award: CA245722; DOI: 10.13039/100000065, name: HHS | NIH | National Institute of Neurological Disorders and Stroke, award: NS08862; DOI: 10.13039/100001024, name: Roy J. Carver Charitable Trust, award: Brenner; DOI: 10.13039/100000875, name: Pew Charitable Trusts, award: Cohen; name: Alfred E. Mann Family Foundation, award: Brenner
Language: English
Date published: 12/25/2020
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; Infectious Disease (Pediatrics); Internal Medicine
Record Identifier: 9984070016302771

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