Restoring NAD+ by NAMPT is essential for the SIRT1/p53-mediated survival of UVA- and UVB-irradiated epidermal keratinocytes

J Photochem Photobiol B. 2021 Aug;221:112238. doi: 10.1016/j.jphotobiol.2021.112238. Epub 2021 Jun 12.

Abstract

Nicotinamide adenine dinucleotide (NAD+) is a crucial coenzyme in energy production. The imbalance of NAD+ synthesis has been found to trigger age-related diseases, such as metabolic disorders, cancer, and neurodegenerative diseases. Also, UV irradiation induces NAD+ depletion in the skin. In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway and essential for NAD+ homeostasis. However, but few studies have focused on the role of NAMPT in response to UV irradiation. Here, we show that NAMPT prevents NAD+ depletion in epidermal keratinocytes to protect against the mild-dose UVA and UVB (UVA/B)-induced proliferation defects. We showed that poly(ADP-ribose) polymerase (PARP) inhibitor rescued the NAD+ depletion in UVA/B-irradiated human keratinocytes, confirming that PAPR transiently exhausts cellular NAD+ to repair DNA damage. Notably, the treatment with a NAMPT inhibitor exacerbated the UVA/B-induced loss of energy production and cell viability. Moreover, the NAMPT inhibitor abrogated the sirtuin-1 (SIRT1)-mediated deacetylation of p53 and significantly inhibited the proliferation of UVA/B-irradiated cells, suggesting that the NAMPT-NAD+-SIRT1 axis regulates p53 functions upon UVA/B stress. The supplementation with NAD+ intermediates, nicotinamide mononucleotide and nicotinamide riboside, rescued the UVA/B-induced phenotypes in the absence of NAMPT activity. Therefore, NAD+ homeostasis is likely essential for the protection of keratinocytes from UV stress in mild doses. Since the skin is continuously exposed to UVA/B irradiation, understanding the protective role of NAMPT in UV stress will help prevent and treat skin photoaging.

Keywords: Nicotinamide adenine dinucleotide; Nicotinamide phosphoribosyltransferase; Normal human epidermal keratinocytes; Poly(ADP-ribose) polymerase; Sirtuin-1; Ultraviolet irradiation.

MeSH terms

  • Acrylamides / chemistry
  • Acrylamides / metabolism
  • Acrylamides / pharmacology
  • Cell Line
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • DNA Damage / radiation effects
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • NAD / metabolism*
  • Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors
  • Nicotinamide Phosphoribosyltransferase / metabolism*
  • Piperidines / chemistry
  • Piperidines / metabolism
  • Piperidines / pharmacology
  • Sirtuin 1 / metabolism*
  • Tumor Suppressor Protein p53 / metabolism*
  • Ultraviolet Rays*

Substances

  • Acrylamides
  • N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
  • Piperidines
  • Tumor Suppressor Protein p53
  • NAD
  • Nicotinamide Phosphoribosyltransferase
  • Sirtuin 1