PUBLICATION

NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death

Authors
Martínez-Morcillo, F.J., Cantón-Sandoval, J., Martínez-Navarro, F.J., Cabas, I., Martínez-Vicente, I., Armistead, J., Hatzold, J., López-Muñoz, A., Martínez-Menchón, T., Corbalán-Vélez, R., Lacal, J., Hammerschmidt, M., García-Borrón, J.C., García-Ayala, A., Cayuela, M.L., Pérez-Oliva, A.B., García-Moreno, D., Mulero, V.
ID
ZDB-PUB-211109-21
Date
2021
Source
PLoS Biology   19: e3001455 (Journal)
Registered Authors
Hammerschmidt, Matthias, Hatzold, Julia, Mulero, Victor
Keywords
none
MeSH Terms
  • Gene Expression Regulation/drug effects
  • Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors
  • Nicotinamide Phosphoribosyltransferase/metabolism*
  • Oxidative Stress/drug effects
  • Oxidative Stress/genetics
  • Poly Adenosine Diphosphate Ribose/metabolism
  • Disease Models, Animal
  • Skin/pathology*
  • Apoptosis Inducing Factor/metabolism
  • Parthanatos*/drug effects
  • Parthanatos*/genetics
  • Cell Nucleus/drug effects
  • Cell Nucleus/metabolism
  • Larva/metabolism
  • Keratinocytes/drug effects
  • Keratinocytes/metabolism
  • Keratinocytes/pathology
  • NAD/metabolism*
  • Proteinase Inhibitory Proteins, Secretory/deficiency
  • Proteinase Inhibitory Proteins, Secretory/metabolism
  • Inflammation/genetics
  • Inflammation/pathology*
  • DNA Damage
  • Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
  • Reactive Oxygen Species/metabolism
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/metabolism
  • Zebrafish
  • Poly(ADP-ribose) Polymerases/metabolism*
  • Cell Proliferation/drug effects
  • Animals
  • Psoriasis/genetics
  • Psoriasis/pathology
  • NADPH Oxidases/antagonists & inhibitors
  • NADPH Oxidases/metabolism
(all 35)
PubMed
34748530 Full text @ PLoS Biol.
Abstract
Several studies have revealed a correlation between chronic inflammation and nicotinamide adenine dinucleotide (NAD+) metabolism, but the precise mechanism involved is unknown. Here, we report that the genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the salvage pathway of NAD+ biosynthesis, reduced oxidative stress, inflammation, and keratinocyte DNA damage, hyperproliferation, and cell death in zebrafish models of chronic skin inflammation, while all these effects were reversed by NAD+ supplementation. Similarly, genetic and pharmacological inhibition of poly(ADP-ribose) (PAR) polymerase 1 (Parp1), overexpression of PAR glycohydrolase, inhibition of apoptosis-inducing factor 1, inhibition of NADPH oxidases, and reactive oxygen species (ROS) scavenging all phenocopied the effects of Nampt inhibition. Pharmacological inhibition of NADPH oxidases/NAMPT/PARP/AIFM1 axis decreased the expression of pathology-associated genes in human organotypic 3D skin models of psoriasis. Consistently, an aberrant induction of NAMPT and PARP activity, together with AIFM1 nuclear translocation, was observed in lesional skin from psoriasis patients. In conclusion, hyperactivation of PARP1 in response to ROS-induced DNA damage, fueled by NAMPT-derived NAD+, mediates skin inflammation through parthanatos cell death.
Genes / Markers
Figures
Figure Gallery (8 images)
Show all Figures
Expression
Phenotype
Fish Conditions Stage Phenotype Figure
ABchemical treatment by environment: olaparibProtruding-mouth
nc1Tg/nc1Tgchemical treatment by environment: FK-866Protruding-mouth
nc1Tg/nc1Tgchemical treatment by environment: FK-866, chemical treatment by environment: NAD(+)Protruding-mouth
nc1Tg/nc1Tgchemical treatment by environment: NAD(+)Protruding-mouth
nc1Tg/nc1Tgchemical treatment by environment: NAD(+)Protruding-mouth
nz50Tg/nz50Tgstandard conditionsProtruding-mouth
nz50Tg/nz50Tgstandard conditionsProtruding-mouth
nz50Tg/nz50Tgchemical treatment by environment: FK-866Protruding-mouth
nz50Tg/nz50Tgchemical treatment by environment: FK-866Protruding-mouth
nz50Tg/nz50Tgchemical treatment by environment: FK-866Protruding-mouth
1 - 10 of 58
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hi2217TgTransgenic Insertion
m14
    		Point Mutation
    nc1TgTransgenic Insertion
      nz50TgTransgenic Insertion
        1 - 4 of 4
        Show
        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        aifm1CRISPR1-aifm1CRISPR
        nampt1CRISPR3-nampt1CRISPR
        nampt2CRISPR4-nampt2CRISPR
        nox1CRISPR3-nox1CRISPR
        nox4CRISPR1-nox4CRISPR
        nox5CRISPR4-nox5CRISPR
        parp1CRISPR8-parp1CRISPR
        1 - 7 of 7
        Show
        Fish
        Fish
        AB
        nc1Tg/nc1Tg
        nz50Tg/nz50Tg
        spint1ahi2217Tg/hi2217Tg
        spint1ahi2217Tg/hi2217Tg; nc1Tg/nc1Tg
        spint1ahi2217Tg/hi2217Tg; nz50Tg/nz50Tg
        spint1ahi2217Tg/hi2217Tg; nz50Tg/nz50Tg + CRISPR1-aifm1
        spint1ahi2217Tg/hi2217Tg; nz50Tg/nz50Tg + CRISPR1-nox4
        spint1ahi2217Tg/hi2217Tg; nz50Tg/nz50Tg + CRISPR3-nox1
        spint1ahi2217Tg/hi2217Tg; nz50Tg/nz50Tg + CRISPR4-nox5
        1 - 10 of 10
        Show
        Antibodies
        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        DsRed2EFGDsRed2
        EGFPEFGEGFP
        1 - 2 of 2
        Show
        Mapping
        Your Input Welcome
        We welcome your input and comments. Please use this form to recommend updates to the information in ZFIN. We appreciate as much detail as possible and references as appropriate. We will review your comments promptly.
        Citation
        Martínez-Morcillo, F.J., Cantón-Sandoval, J., Martínez-Navarro, F.J., Cabas, I., Martínez-Vicente, I., Armistead, J., Hatzold, J., López-Muñoz, A., Martínez-Menchón, T., Corbalán-Vélez, R., Lacal, J., Hammerschmidt, M., García-Borrón, J.C., García-Ayala, A., Cayuela, M.L., Pérez-Oliva, A.B., García-Moreno, D., Mulero, V. (2021) NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death. PLoS Biology. 19:e3001455.