The bacterial fermentation product butyrate influences epithelial signaling via reactive oxygen species-mediated changes in cullin-1 neddylation.
The bacterial fermentation product butyrate influences epithelial signaling via reactive oxygen species-mediated changes in cullin-1 neddylation.
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DOI：
10.4049/jimmunol.182.1.538
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发表时间：
2009-01-01
期刊：
影响因子：
--
通讯作者：
Neish AS
中科院分区：
文献类型：
--
作者：
Kumar A;Wu H;Collier-Hyams LS;Kwon YM;Hanson JM;Neish AS
人体肠道菌群在肠道健康和疾病中起着重要作用。肠道细菌群可以通过阻断IκB泛素化来抑制NF-κB途径，这一过程是由E3-SCFα-TrCP泛素连接酶催化的。这种泛素连接酶的活性是通过类泛素蛋白NEDD8对cullin-1亚基的共价修饰来调节的。我们先前报道，活的共生细菌与哺乳动物肠道上皮细胞的相互作用导致快速和可逆的活性氧物种(ROS)的产生，从而调节CULLIN-1的缺失，并导致对NF-κB途径的抑制效应。在这里，我们证明了丁酸盐和其他短链脂肪酸在体外模拟人肠上皮细胞和人体组织时会导致缺陷型CUL-1的丢失，并表明生理浓度的丁酸调节E3-SCFβ-TrCP泛素连接酶的泛素化和降解，靶标是核因子-κB抑制物IκB-α。从机理上讲，我们证明了丁酸的生理浓度诱导了活性氧物种，从而瞬时改变了细胞内的氧化还原平衡，并导致NEDD8结合酶Ubc12的失活，其方式类似于活菌介导的影响。由于正常菌群产生大量的丁酸和其他短链脂肪酸，这些数据提供了肠道正常菌群的天然产物与重要的上皮炎症和增殖信号通路之间的功能联系。
The human enteric flora plays a significant role in intestinal health and disease. Populations of enteric bacteria can inhibit the NF-κB pathway by blockade of IκB-α ubiquitination, a process catalyzed by the E3-SCFβ-TrCP ubiquitin ligase. The activity of this ubiquitin ligase is regulated via covalent modification of the Cullin-1 subunit by the ubiquitin-like protein NEDD8. We previously reported that interaction of viable commensal bacteria with mammalian intestinal epithelial cells resulted in a rapid and reversible generation of reactive oxygen species (ROS) that modulated neddylation of Cullin-1 and resulted in suppressive effects on the NF-κB pathway. Herein, we demonstrate that butyrate and other short chain fatty acids supplemented to model human intestinal epithelia in vitro and human tissue ex vivo results in loss of neddylated Cul-1 and show that physiological concentrations of butyrate modulate the ubiquitination and degradation of a target of the E3-SCFβ-TrCP ubiquitin ligase, the NF-κB inhibitor IκB-α. Mechanistically, we show that physiological concentrations of butyrate induces reactive oxygen species that transiently alters the intracellular redox balance and results in inactivation of the NEDD8-conjugating enzyme Ubc12 in a manner similar to effects mediated by viable bacteria. Because the normal flora produces significant amounts of butyrate and other short chain fatty acids, these data provide a functional link between a natural product of the intestinal normal flora and important epithelial inflammatory and proliferative signaling pathways.
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