Increased S-nitrosylation and proteasomal degradation of caspase-3 during infection contribute to the persistence of adherent invasive Escherichia coli (AIEC) in immune cells.
Increased S-nitrosylation and proteasomal degradation of caspase-3 during infection contribute to the persistence of adherent invasive Escherichia coli (AIEC) in immune cells.
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DOI：
10.1371/journal.pone.0068386
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wall DM
中科院分区：
文献类型：
--
作者：
Dunne KA;Allam A;McIntosh A;Houston SA;Cerovic V;Goodyear CS;Roe AJ;Beatson SA;Milling SW;Walker D;Wall DM
粘附性侵袭性大肠杆菌（AIEC）被认为是克罗恩病（CD）的病原体，因为它们从CD患者的肠道中分离出来，并且它们能够持续存在于诱导肉芽肿的巨噬细胞中。AIEC的细胞内快速增殖使其与其他肠道病原体（如鼠伤寒沙门氏菌）区别开来，后者在有限复制后诱导程序性细胞死亡（PCD）。了解感染细胞对AIEC细菌负荷增加和相关代谢应激的反应可能有助于深入了解AIEC的发病机制及其与CD的关系。本研究表明，AIEC在巨噬细胞和树突状细胞内的持久性可以通过增加caspase-3的蛋白酶体降解来促进。此外，在AIEC感染的巨噬细胞中，可以抑制酶活性的caspase-3的前体和活性形式的s -亚硝基化增加。这种s -亚硝基化的caspase-3在蛋白酶体的抑制下积累，表明s -亚硝基化在以独立于泛素化的方式诱导caspase-3降解中的额外作用。除了与CD相关的自噬性遗传缺陷外，AIEC感染细胞通过增加caspase-3降解介导的细胞凋亡延迟可能是CD患者持续时间延长的重要因素。
Adherent invasive Escherichia coli (AIEC) have been implicated as a causative agent of Crohn’s disease (CD) due to their isolation from the intestines of CD sufferers and their ability to persist in macrophages inducing granulomas. The rapid intracellular multiplication of AIEC sets it apart from other enteric pathogens such as Salmonella Typhimurium which after limited replication induce programmed cell death (PCD). Understanding the response of infected cells to the increased AIEC bacterial load and associated metabolic stress may offer insights into AIEC pathogenesis and its association with CD. Here we show that AIEC persistence within macrophages and dendritic cells is facilitated by increased proteasomal degradation of caspase-3. In addition S-nitrosylation of pro- and active forms of caspase-3, which can inhibit the enzymes activity, is increased in AIEC infected macrophages. This S-nitrosylated caspase-3 was seen to accumulate upon inhibition of the proteasome indicating an additional role for S-nitrosylation in inducing caspase-3 degradation in a manner independent of ubiquitination. In addition to the autophagic genetic defects that are linked to CD, this delay in apoptosis mediated in AIEC infected cells through increased degradation of caspase-3, may be an essential factor in its prolonged persistence in CD patients.
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