Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1833, Issue 8, Pages 1985-1991Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2013.04.005
Keywords
Acetylation; Astrocyte; NAD(+); NF-kappa B; PARP-1; SIRT1
Categories
Funding
- NIA NIH HHS [R01 AG033017, P01 AG019724, P50 AG023501, R01 AG036884] Funding Source: Medline
- NINDS NIH HHS [R01 NS041421] Funding Source: Medline
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NF-kappa B is a transcription factor that integrates pro-inflammatory and pro-survival responses in diverse cell types. The activity of NF-kappa B is regulated in part by acetylation of its p65 subunit at lysine 310, which is required for transcription complex formation. De-acetylation at this site is performed by sirtuin 1 (SIRT1) and possibly other sirtuins in an NAD(+) dependent manner, such that SIRT1 inhibition promotes NF-kappa B transcriptional activity. It is unknown, however, whether changes in NAD(+) levels can influence p65 acetylation and cellular inflammatory responses. Poly(ADP-ribose)-1 (PARP-1) is an abundant nuclear enzyme that consumes NAD(+) in the process of forming (ADP-ribose)polymers on target proteins, and extensive PARP-1 activation can reduce intracellular NAD(+) concentrations. Here we tested the idea that PARP-1 activation can regulate NF-kappa B transcriptional activity by reducing NAD(+) concentrations and thereby inhibiting de-acetylation of p65. Primary astrocyte cultures were treated with the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) to induce PARP-1 activation. This resulted in sustained acetylation of p65 and increased NF-kappa B transcriptional activity as monitored by a kappa B-driven eGFP reporter gene. These effects of MNNG were negated by a PARP-1 inhibitor, in PARP-1(-/-) cells, and in PARP-1(-/-) cells transfected with a catalytically inactive PARP-1 construct, thus confirming that these effects are mediated by PARP-1 catalytic activity. The effects of PARP-1 activation were replicated by a SIRT1 inhibitor, EX-527, and were reversed by exogenous NAD(+). These findings demonstrate that PARP-1-induced changes in NAD(+) levels can modulate NF-kappa B transcriptional activity through effects on p65 acetylation. (C) 2013 Elsevier B.V. All rights reserved.
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