High-mobility group box 1 is a novel deacetylation target of Sirtuin1.
High-mobility group box 1 is a novel deacetylation target of Sirtuin1.
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DOI：
10.1038/ki.2014.217
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发表时间：
2015-01
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
--
作者：
高迁移率族蛋白1（HMGB1）经历乙酰化，核到细胞质的易位和从应激肾脏释放，释放导致全身炎症的事件的信号级联反应。在这里，我们测试了Sirtuin1（SIRT1）的脱乙酰酶活性是否参与调节HMGB1的核保留，以最终调节应激期间HMGB1分泌引发的损伤信号。当免疫沉淀的乙酰化HMGB1与SIRT 1孵育时，HMGB1乙酰化降低了57%。蛋白质组学分析显示，SIRT1在HMGB1的促炎和核定位信号结构域内的四个赖氨酸残基（55、88、90和177）处使HMGB1脱乙酰基。内皮细胞中SIRT1的基因消融或药物抑制增加了HMGB1乙酰化和易位。在体内，SIRT1的缺失减少了核HMGB1，同时增加了其乙酰化并在基础和缺血条件下释放到循环中，导致肾损伤增加。相反，白藜芦醇预处理导致HMGB1乙酰化减少，其核保留，减少全身释放和减少肾小管损伤。因此，一个恶性循环开始运转，其中炎症诱导的SIRT1抑制使HMGB1的脱乙酰化失效，促进其核到细胞质的易位和全身释放，从而维持炎症。
High mobility group box 1 (HMGB1) undergoes acetylation, nuclear-to-cytoplasmic translocation and release from stressed kidneys, unleashing a signaling cascade of events leading to systemic inflammation. Here we tested whether the deacetylase activity of Sirtuin1 (SIRT1) participates in regulating nuclear retention of HMGB1 to ultimately modulate damage signaling initiated by HMGB1 secretion during stress. When immunoprecipitated acetylated HMGB1 was incubated with SIRT1, HMGB1 acetylation decreased by 57%. Proteomic analysis showed that SIRT1 deacetylates HMGB1 at four lysine residues (55, 88, 90 and 177) within the pro-inflammatory and nuclear localization signal domains of HMGB1. Genetic ablation or pharmacological inhibition of SIRT1 in endothelial cells increased HMGB1 acetylation and translocation. In vivo, deletion of SIRT1 reduced nuclear HMGB1 while increasing its acetylation and release into circulation during basal and ischemic conditions causing increased renal damage. Conversely, resveratrol pretreatment led to decreased HMGB1 acetylation, its nuclear retention, decreased systemic release and reduced tubular damage. Thus, a vicious cycle is set into motion in which the inflammation-induced repression of SIRT1 disables deacetylation of HMGB1, facilitates its nuclear-to-cytoplasmic translocation and systemic release, thereby maintaining inflammation.
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影响因子：
3.7
作者：
Mullins, GE;Sunden-Cullberg, J;Treutiger, CJ
通讯作者：
Treutiger, CJ
影响因子：
20.1
作者：
Brodsky, SV;Gealekman, O;Goligorsky, MS
通讯作者：
Goligorsky, MS
影响因子：
3.1
作者：
Dhupar, Rajeev;Klune, John R.;Tsung, Allan
通讯作者：
Tsung, Allan
影响因子：
6.1
作者：
Do Amaral, Catia Lira;Francescato, Heloisa Della Coletta;Pires Bianchi, Maria De Lourdes
通讯作者：
Pires Bianchi, Maria De Lourdes
影响因子：
4.8
作者：
Evankovich, John;Cho, Sung W.;Tsung, Allan
通讯作者：
Tsung, Allan