NAD+-dependent SIRT1 Deacetylase Participates in Epigenetic Reprogramming during Endotoxin Tolerance
NAD+-dependent SIRT1 Deacetylase Participates in Epigenetic Reprogramming during Endotoxin Tolerance
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DOI：
10.1074/jbc.m110.196790
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发表时间：
2011-03-18
影响因子：
4.8
通讯作者：
Mccall, Charles E.
中科院分区：
文献类型：
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作者：
Liu, Tie Fu;Yoza, Barbara K.;Mccall, Charles E.
当Toll样受体(TLR)识别并响应威胁生命的全身性感染时，基因选择性表观遗传重新编程和细胞生物能量学的转变就会发生。利用内毒素耐受的人单核细胞模型和急性全身炎症合并脓毒症的人白细胞，我们报告了能量传感器sirtuin 1(SIRT1)协调表观遗传和生物能量转移。TLR4信号转导后，SIRT1在TNF-α和IL-β启动子处迅速聚集，而不是I-kappa Bα；SIRT1启动子的结合依赖于其辅助因子NAD(+)。在这个最初的过程中，SIRT1去乙酰化了RelA/P65赖氨酸310和核小体组蛋白H4赖氨酸16，以促进依赖于核因子kappaB的转录的终止。然后，SIRT1保持启动子结合，并招募从头诱导的RelB，它指导成熟的转录抑制物复合体的组装，从而产生内毒素耐受。SIRT1还促进了RelB的从头表达。在持续内毒素耐受过程中，内源性产生NAD(+)的限速酶烟酰胺磷酸核糖基转移酶(NAMPT)和SIRT1表达增加。SIRT1的上调需要蛋白质的稳定和翻译的加强。为了支持生物能量在人类败血症中的协调作用，我们观察到内毒素耐受脓毒症血白细胞的肿瘤坏死因子-α启动子上伴随着SIRT1和RelB积聚的NAD(+)水平升高。我们得出结论，TLR4刺激和人类败血症激活了将NAD(+)及其传感器SIRT1与表观遗传重编程偶联的通路。
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-alpha and IL-beta, but not I kappa B alpha; 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 NF kappa B-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-alpha 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.