NAD(+)-dependent SIRT1 Deacetylase Participates in Epigenetic Reprogramming during Endotoxin Tolerance

Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2011; 286(11):9856-64. DOI: 10.1074/jbc.M110.196790
Source: PubMed


Gene-selective epigenetic reprogramming and shifts in cellular bioenergetics develop when Toll-like receptors (TLR) recognize
and respond to systemic life-threatening infections. Using a human monocyte cell model of endotoxin tolerance and human leukocytes
from acute systemic inflammation with sepsis, we report that energy sensor sirtuin 1 (SIRT1) coordinates the epigenetic and
bioenergy shifts. After TLR4 signaling, SIRT1 rapidly accumulated at the promoters of TNF-α and IL-1β, but not IκBα; SIRT1
promoter binding was dependent on its co-factor, NAD+. During this initial process, SIRT1 deacetylated RelA/p65 lysine 310 and nucleosomal histone H4 lysine 16 to promote termination
of NFκB-dependent transcription. SIRT1 then remained promoter bound and recruited de novo induced RelB, which directed assembly of the mature transcription repressor complex that generates endotoxin tolerance. SIRT1
also promoted de novo expression of RelB. During sustained endotoxin tolerance, nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting
enzyme for endogenous production of NAD+, and SIRT1 expression increased. The elevation of SIRT1 required protein stabilization and enhanced translation. To support
the coordination of bioenergetics in human sepsis, we observed elevated NAD+ levels concomitant with SIRT1 and RelB accumulation at the TNF-α promoter of endotoxin tolerant sepsis blood leukocytes.
We conclude that TLR4 stimulation and human sepsis activate pathways that couple NAD+ and its sensor SIRT1 with epigenetic reprogramming.

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Available from: Charles E Mccall, Aug 29, 2015
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    • "Emerging evidence indicates that the SIRT family of NAD + sensors is critically involved in linking metabolism and inflammation (Liu et al., 2012a; Liu et al., 2011; Yeung et al., 2004). The increased NAD + levels brought about by the Nampt salvage pathway in mammalian cells activate SIRT1 to deacetylate and inactivate NF-kB p65, thereby terminating inflammatory responses (Liu et al., 2011; Yeung et al., 2004). Aside from the "
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    • "Second, Sirt1 may directly modulate NF-κB-dependent immune responses and coupled ROS production by deacetylating p65 [95]. And third, Sirt1 can negatively regulate the expression of TNFα and IL-1β by binding to specific sites in their promoters [96]. Further connections between Sirt1, TLRs and inflammasomes include Sirt1 downregulation by palmitate-induced miR-195 and Sirt1 cleavage by caspase-1 [92, 97]. "
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    • "During endotoxin tolerance when transition from hyperinflammation to hypoinflammation occurs, SIRT1 deacetylates H4K16 to terminate NF-κB-dependent transcription. SIRT1 represses gene expression by deacetylating histones and also by remaining bound to TNFα and IL-1β promoter regions to recruit more components of repressor complexes, such as histone H1, RelB, and methyltransferases (Liu et al., 2011; Figure 2). "
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