Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages.
Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages.
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DOI：
10.1371/journal.ppat.0030111
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发表时间：
2007-08-10
期刊：
影响因子：
6.7
通讯作者：
Nuñez G
中科院分区：
文献类型：
--
作者：
Suzuki T;Franchi L;Toma C;Ashida H;Ogawa M;Yoshikawa Y;Mimuro H;Inohara N;Sasakawa C;Nuñez G
志贺氏菌感染，细菌性痢疾的原因，诱导半胱天冬酶-1激活和细胞死亡的巨噬细胞，但这种激活的确切机制仍然知之甚少。我们在此证明志贺氏菌诱导的caspase-1激活和IL-1β加工是通过Ipaf介导的，Ipaf是核苷酸结合寡聚化结构域（NOD）样受体（NLR）家族的胞浆模式识别受体，以及含有C末端caspase募集结构域（ASC）的衔接蛋白--凋亡相关斑点样蛋白。我们还表明，Ipaf是关键的pyroptosis，一个专门的形式的半胱天冬酶-1依赖性细胞死亡诱导的巨噬细胞由细菌感染，而ASC是不可逆的。与沙门氏菌和军团菌中观察到的不同，志贺氏菌感染诱导的caspase-1激活不依赖于鞭毛蛋白。值得注意的是，志贺氏菌感染的巨噬细胞诱导自噬，这是显着增加的情况下，胱天蛋白酶-1或Ipaf，但不是ASC。志贺氏菌诱导的自噬需要一个完整的细菌III型分泌系统，但不是VirG蛋白，一种在上皮感染细胞中自噬所需的细菌因子。用自噬抑制剂3-甲基腺嘌呤处理巨噬细胞，增强志贺氏菌感染诱导的焦亡，表明自噬保护受感染的巨噬细胞免于焦亡。因此，Ipaf在志贺氏菌诱导的caspase-1活化中起着关键作用，独立于鞭毛蛋白。此外，Ipaf或半胱天冬酶-1，但不是ASC的情况下，调节热凋亡和诱导志贺氏菌感染的巨噬细胞中的自噬，提供了一个新的功能，NLR蛋白在细菌-宿主相互作用。 志贺氏菌是细菌病原体，是细菌性痢疾的原因，称为志贺氏菌病。志贺氏菌致病倾向的一个关键方面在于它能够侵入上皮细胞和巨噬细胞的细胞质。巨噬细胞的细菌入侵诱导焦亡，与半胱天冬酶-1活化相关的促炎性细胞死亡。活化的半胱天冬酶-1然后切割并活化白细胞介素原（proIL）-1β和proIL-18，它们是参与宿主炎症反应的促炎细胞因子。然而，志贺氏菌感染诱导的caspase-1激活的确切机制仍然知之甚少。Ipaf是核苷酸结合寡聚化结构域（NOD）样受体（NLR）家族的一种胞质模式识别受体，是一种重要的宿主因子，通过感知某些细菌（如沙门氏菌或军团菌）产生的鞭毛蛋白来激活caspase-1。我们发现，Ipaf和衔接蛋白ASC所需的caspase-1激活诱导的非鞭毛志贺氏菌感染。因此，Ipaf和ASC通过感应未知的细菌因子而不是鞭毛蛋白介导半胱天冬酶-1活化。自噬是一种消除细胞内病原体的细胞系统，在志贺氏菌感染的巨噬细胞中，caspase-1或Ipaf的缺乏显著增强，但ASC不增强。自噬的抑制促进志贺氏菌诱导的细胞死亡，表明自噬保护感染的巨噬细胞免于焦亡。这项研究提供的证据表明，在志贺氏菌感染的巨噬细胞中，自噬被Ipaf和caspase-1抑制，但受到ASC的正调控，为NLR蛋白在细菌-宿主相互作用中提供了新的功能。
Shigella infection, the cause of bacillary dysentery, induces caspase-1 activation and cell death in macrophages, but the precise mechanisms of this activation remain poorly understood. We demonstrate here that caspase-1 activation and IL-1β processing induced by Shigella are mediated through Ipaf, a cytosolic pattern-recognition receptor of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, and the adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC). We also show that Ipaf was critical for pyroptosis, a specialized form of caspase-1-dependent cell death induced in macrophages by bacterial infection, whereas ASC was dispensable. Unlike that observed in Salmonella and Legionella, caspase-1 activation induced by Shigella infection was independent of flagellin. Notably, infection of macrophages with Shigella induced autophagy, which was dramatically increased by the absence of caspase-1 or Ipaf, but not ASC. Autophagy induced by Shigella required an intact bacterial type III secretion system but not VirG protein, a bacterial factor required for autophagy in epithelial-infected cells. Treatment of macrophages with 3-methyladenine, an inhibitor of autophagy, enhanced pyroptosis induced by Shigella infection, suggesting that autophagy protects infected macrophages from pyroptosis. Thus, Ipaf plays a critical role in caspase-1 activation induced by Shigella independently of flagellin. Furthermore, the absence of Ipaf or caspase-1, but not ASC, regulates pyroptosis and the induction of autophagy in Shigella-infected macrophages, providing a novel function for NLR proteins in bacterial–host interactions. Shigella are bacterial pathogens that are the cause of bacillary dysentery known as shigellosis. A crucial aspect of the propensity of Shigella to cause diseases lies in its ability to invade the cytoplasm of epithelial cells as well as macrophages. The bacterial invasion of macrophages induces pyroptosis, the proinflammatory cell death associated with caspase-1 activation. Activated caspase-1 then cleaves and activates prointerleukin (proIL)-1β and proIL-18, which are proinflammatory cytokines involved in host inflammatory responses. However, the precise mechanisms of caspase-1 activation induced by Shigella infection remain poorly understood. Ipaf, a cytosolic pattern-recognition receptor of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, is a crucial host factor that activates caspase-1 through the sensing of flagellin produced by some bacteria, such as Salmonella or Legionella. We discovered that Ipaf and the adaptor protein ASC are required for caspase-1 activation induced by non-flagellated Shigella infection. Thus, Ipaf and ASC mediate caspase-1 activation by sensing an unknown bacterial factor, but not flagellin. Autophagy, a cellular system for eliminating intracellular pathogens, was dramatically enhanced in Shigella-infected macrophages by the absence of caspase-1 or Ipaf, but not ASC. The inhibition of autophagy promoted Shigella-induced cell death, suggesting that autophagy protects infected macrophages from pyroptosis. This study provides evidence that in Shigella-infected macrophages, autophagy is inhibited by Ipaf and caspase-1, but positively regulated by ASC, providing a novel function for NLR proteins in bacterial–host interactions.
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影响因子：
3.4
作者：
Amer, AO;Swanson, MS
通讯作者：
Swanson, MS
影响因子：
4.4
作者：
Lamkanfi, Mohamed;Amer, Amal;Nunez, Gabriel
通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
30.5
作者：
Franchi, Luigi;Amer, Amal;Nunez, Gabriel
通讯作者：
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DOI：
10.1073/pnas.120163297
发表时间：
2000-06-06
影响因子：
11.1
作者：
Datsenko, KA;Wanner, BL
通讯作者：
Wanner, BL