| First Author | Kauppinen TM | Year | 2013 |
| Journal | Biochim Biophys Acta | Volume | 1833 |
| Issue | 8 | Pages | 1985-91 |
| PubMed ID | 23597856 | Mgi Jnum | J:202394 |
| Mgi Id | MGI:5518979 | Doi | 10.1016/j.bbamcr.2013.04.005 |
| Citation | Kauppinen TM, et al. (2013) Poly(ADP-ribose) polymerase-1-induced NAD(+) depletion promotes nuclear factor-kappaB transcriptional activity by preventing p65 de-acetylation. Biochim Biophys Acta 1833(8):1985-91 |
| abstractText | NF-kappaB is a transcription factor that integrates pro-inflammatory and pro-survival responses in diverse cell types. The activity of NF-kappaB 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-kappaB 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-kappaB 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-kappaB transcriptional activity as monitored by a kappaB-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-kappaB transcriptional activity through effects on p65 acetylation. |
