Shigella type III secretion protein MxiI is recognized by Naip2 to induce Nlrc4 inflammasome activation independently of Pkcδ.
Shigella type III secretion protein MxiI is recognized by Naip2 to induce Nlrc4 inflammasome activation independently of Pkcδ.
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DOI：
10.1371/journal.ppat.1003926
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发表时间：
2014-02
期刊：
影响因子：
6.7
通讯作者：
Núñez G
中科院分区：
文献类型：
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作者：
Suzuki S;Franchi L;He Y;Muñoz-Planillo R;Mimuro H;Suzuki T;Sasakawa C;Núñez G
核苷酸结合结构域和富含亮氨酸重复序列（NLR）家族成员对细胞内病原菌的识别会触发针对细菌感染的免疫反应。几种革兰氏阴性菌诱导的一种主要反应是通过Nlrc4炎症小体激活半胱天冬酶 - 1。激活后，半胱天冬酶 - 1调节前白细胞介素 - 1β和前白细胞介素 - 18的加工过程，导致成熟白细胞介素 - 1β和白细胞介素 - 18的释放以及细胞焦亡的诱导。Nlrc4炎症小体的激活需要完整的III型或IV型分泌系统的存在，该系统介导少量鞭毛蛋白或PrgJ样杆状蛋白转运到宿主细胞质中以诱导Nlrc4激活。利用沙门氏菌系统，研究表明Naip2和Naip5分别将鞭毛蛋白和杆状蛋白PrgJ与Nlrc4连接起来。此外，发现蛋白激酶Cδ（Pkcδ）对Nlrc4的丝氨酸533位点进行磷酸化对于Nlrc4炎症小体的激活至关重要。在此，我们表明Naip2识别志贺氏菌III型分泌系统（T3SS）内杆状蛋白MxiI并诱导Nlrc4炎症小体激活。MxiI在原代巨噬细胞中的表达足以诱导细胞焦亡和白细胞介素 - 1β的释放，而在缺乏Nlrc4的巨噬细胞中这些过程被阻止。在MxiI存在或志贺氏菌感染的情况下，MxiI与Naip2结合，并且Naip2与Nlrc4相互作用。小干扰RNA介导的Naip2（而非Naip5）的敲低抑制了志贺氏菌诱导的半胱天冬酶 - 1激活、白细胞介素 - 1β成熟以及Asc焦亡体形成。值得注意的是，对于志贺氏菌或沙门氏菌感染诱导的半胱天冬酶 - 1激活和白细胞介素 - 1β分泌，蛋白激酶Cδ是不必要的。这些结果表明，志贺氏菌对半胱天冬酶 - 1的激活是由杆状蛋白MxiI触发的，MxiI与Naip2相互作用以独立于蛋白激酶Cδ诱导Nlrc4炎症小体的激活。
志贺氏菌是引起细菌性痢疾的病原菌。志贺氏菌的一个重要特征是它们能够侵入宿主上皮细胞和巨噬细胞的细胞质。宿主识别志贺氏菌入侵的一个主要组成部分是炎症小体的激活，炎症小体是一种在巨噬细胞中驱动半胱天冬酶 - 1激活的分子平台。尽管已知志贺氏菌会诱导Nlrc4炎症小体的激活，但该细菌激活Nlrc4的机制在很大程度上是未知的。我们发现志贺氏菌III型分泌系统内杆状蛋白MxiI通过与宿主Naip2的相互作用诱导Nlrc4炎症小体激活，这促进了巨噬细胞中Naip2与Nlrc4的结合。MxiI的表达诱导半胱天冬酶 - 1激活、Asc寡聚化、细胞焦亡以及白细胞介素 - 1β释放，这些过程需要Naip2，但不需要Naip5。重要的是，志贺氏菌感染诱导的半胱天冬酶 - 1激活不受蛋白激酶Cδ缺乏的影响。这项研究阐明了在志贺氏菌感染的巨噬细胞中驱动Nlrc4炎症小体激活的微生物 - 宿主相互作用。
Recognition of intracellular pathogenic bacteria by members of the nucleotide-binding domain and leucine-rich repeat containing (NLR) family triggers immune responses against bacterial infection. A major response induced by several Gram-negative bacteria is the activation of caspase-1 via the Nlrc4 inflammasome. Upon activation, caspase-1 regulates the processing of proIL-1β and proIL-18 leading to the release of mature IL-1β and IL-18, and induction of pyroptosis. The activation of the Nlrc4 inflammasome requires the presence of an intact type III or IV secretion system that mediates the translocation of small amounts of flagellin or PrgJ-like rod proteins into the host cytosol to induce Nlrc4 activation. Using the Salmonella system, it was shown that Naip2 and Naip5 link flagellin and the rod protein PrgJ, respectively, to Nlrc4. Furthermore, phosphorylation of Nlrc4 at Ser533 by Pkcδ was found to be critical for the activation of the Nlrc4 inflammasome. Here, we show that Naip2 recognizes the Shigella T3SS inner rod protein MxiI and induces Nlrc4 inflammasome activation. The expression of MxiI in primary macrophages was sufficient to induce pyroptosis and IL-1β release, which were prevented in macrophages deficient in Nlrc4. In the presence of MxiI or Shigella infection, MxiI associated with Naip2, and Naip2 interacted with Nlrc4. siRNA-mediated knockdown of Naip2, but not Naip5, inhibited Shigella-induced caspase-1 activation, IL-1β maturation and Asc pyroptosome formation. Notably, the Pkcδ kinase was dispensable for caspase-1 activation and secretion of IL-1β induced by Shigella or Salmonella infection. These results indicate that activation of caspase-1 by Shigella is triggered by the rod protein MxiI that interacts with Naip2 to induce activation of the Nlrc4 inflammasome independently of the Pkcδ kinase. Shigella are bacterial pathogens that are the cause of bacillary dysentery. An important feature of Shigella is their ability to invade the cytoplasm of host epithelial cells and macrophages. A major component of host recognition of Shigella invasion is the activation of the inflammasome, a molecular platform that drives the activation of caspase-1 in macrophages. Although Shigella is known to induce the activation of the Nlrc4 inflammasome, the mechanism by which the bacterium activates Nlrc4 is largely unknown. We discovered that the Shigella T3SS inner rod protein MxiI induces Nlrc4 inflammasome activation through the interaction with host Naip2, which promoted the association of Naip2 with Nlrc4 in macrophages. Expression of MxiI induced caspase-1 activation, Asc oligomerization, pyroptosis and IL-1β release which required Naip2, but not Naip5. Significantly, caspase-1 activation induced by Shigella infection was unaffected by deficiency of the Pkcδ kinase. This study elucidates the microbial-host interactions that drive the activation of the Nlrc4 inflammasome in Shigella-infected macrophages.
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影响因子：
8.7
作者：
Broz P;Monack DM
通讯作者：
Monack DM
DOI：
10.1073/pnas.0913087107
发表时间：
2010-02-16
影响因子：
11.1
作者：
Miao, Edward A.;Mao, Dat P.;Aderem, Alan
通讯作者：
Aderem, Alan
影响因子：
30.5
作者：
Franchi, Luigi;Amer, Amal;Nunez, Gabriel
通讯作者：
Nunez, Gabriel
影响因子：
30.5
作者：
通讯作者：
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影响因子：
30.5
作者：
通讯作者：
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