TY - JOUR
T1 - Coronavirus infection and PARP expression dysregulate the NAD metabolome
T2 - An actionable component of innate immunity
AU - Heer, Collin D.
AU - Sanderson, Daniel J.
AU - Voth, Lynden S.
AU - Alhammad, Yousef M.O.
AU - Schmidt, Mark S.
AU - Trammell, Samuel A.J.
AU - Perlman, Stanley
AU - Cohen, Michael S.
AU - Fehr, Anthony R.
AU - Brenner, Charles
N1 - Funding Information:
This work was supported by NHLBI, National Institutes of Health Grant HL147545 (to C. B.); NIGMS, National Institutes of Health Grants GM008629 (to S. A. J. T.) and GM113117 (to A. R. F.); NIAID, National Institutes of Health Grants AI134993 (to A. R. F.) and AI060699 and AI091322 (to S. P.); NCI, National Institutes of Health Grant CA245722 (to C. D. H.); NINDS, National Institutes of Health Grant 1NS08862 (M. S. C.); Roy J. Carver Trust (to C. B.); Alfred E. Mann Family Foundation (to C. B.); and Pew Charitable Trusts (to M. S. C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
Funding and additional information—This work was supported by NHLBI, National Institutes of Health Grant HL147545 (to C. B.); NIGMS, National Institutes of Health Grants GM008629 (to S. A. J. T.) and GM113117 (to A. R. F.); NIAID, National Institutes of Health Grants AI134993 (to A. R. F.) and AI060699 and AI091322 (to S. P.); NCI, National Institutes of Health Grant CA245722 (to C. D. H.); NINDS, National Institutes of Health Grant 1NS08862 (M. S. C.); Roy J. Carver Trust (to C. B.); Alfred E. Mann Family Foundation (to C. B.); and Pew Charitable Trusts (to M. S. C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2020 Heer et al.
PY - 2020/12/25
Y1 - 2020/12/25
N2 - 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 NAD1 and NADP1. 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.
AB - 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 NAD1 and NADP1. 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.
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U2 - 10.1074/jbc.RA120.015138
DO - 10.1074/jbc.RA120.015138
M3 - Article
C2 - 33051211
AN - SCOPUS:85098269852
SN - 0021-9258
VL - 295
SP - 17986
EP - 17996
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 52
ER -