Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity.
Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity.
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DOI：
10.1038/nature10394
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发表时间：
2011-08-28
期刊：
影响因子：
64.8
通讯作者：
Vance, Russell E.
中科院分区：
文献类型：
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作者：
Kofoed, Eric M.;Vance, Russell E.
炎性小体是一个胞质多蛋白复合物家族，其通过激活CASPASE 1（CASP 1）蛋白酶来启动对病原微生物的先天免疫应答。虽然遗传数据支持炎性小体在免疫防御和炎性疾病中的关键作用，但个体炎性小体对特定刺激物反应的分子基础仍然知之甚少。含有NLRC 4（NLR家族，含有C4的CARD结构域）蛋白的炎性体先前显示响应于两种不同的细菌蛋白（鞭毛蛋白和PrgJ，病原体相关的III型分泌系统的保守组分）而被激活。然而，NLRC 4和鞭毛蛋白或PrgJ之间的直接结合从未得到证实。NLRC 4的同源物NAIP 5（NLR家族，凋亡抑制蛋白5）已经涉及NLRC 4的活化，但是被广泛认为仅起辅助作用，因为NAIP 5通常与NLRC 4活化相关。然而，Naip 5是一个小的多基因家族的成员，提高了Naip基因之间的冗余和功能特化的可能性。事实上，我们在这里表明，不同的NAIP旁系同源物决定了不同的细菌配体的NLRC 4炎性体的特异性。特别是，我们发现细菌PrgJ激活内源性NLRC 4需要NAIP 2，NAIP基因家族的一个先前未表征的成员，而NAIP 5和NAIP 6激活NLRC 4特异性响应细菌鞭毛蛋白。我们通过使用重建的NLRC 4炎性小体系统，剖析了NAIP蛋白需求的生化机制。我们发现NAIP蛋白控制NLRC 4的配体依赖性寡聚化，并且NAIP 2/NLRC 4与PrgJ物理关联，但不与鞭毛蛋白关联，而NAIP 5/NLRC 4与鞭毛蛋白关联，但不与PrgJ关联。总之，我们的研究结果确定NAIP作为免疫传感器蛋白，并提供了一个简单的受体-配体模型激活的NAIP/NLRC 4炎性小体的生化证据。
Inflammasomes are a family of cytosolic multiprotein complexes that initiate innate immune responses to pathogenic microbes by activating the CASPASE1 (CASP1) protease. Although genetic data support a critical role for inflammasomes in immune defense and inflammatory diseases, the molecular basis by which individual inflammasomes respond to specific stimuli remains poorly understood. The inflammasome that contains the NLRC4 (NLR family, CARD domain containing C4) protein was previously shown to be activated in response to two distinct bacterial proteins, flagellin and PrgJ, a conserved component of pathogen-associated type III secretion systems. However, direct binding between NLRC4 and flagellin or PrgJ has never been demonstrated. A homolog of NLRC4, NAIP5 (NLR family, Apoptosis Inhibitory Protein 5), has been implicated in activation of NLRC4, but is widely assumed to play only an auxiliary role, since NAIP5 is often dispensable for NLRC4 activation. However, Naip5 is a member of a small multigene family, raising the possibility of redundancy and functional specialization among Naip genes. Indeed, we show here that different NAIP paralogs dictate the specificity of the NLRC4 inflammasome for distinct bacterial ligands. In particular, we found that activation of endogenous NLRC4 by bacterial PrgJ requires NAIP2, a previously uncharacterized member of the NAIP gene family, whereas NAIP5 and NAIP6 activate NLRC4 specifically in response to bacterial flagellin. We dissected the biochemical mechanism underlying the requirement for NAIP proteins by use of a reconstituted NLRC4 inflammasome system. We found that NAIP proteins control ligand-dependent oligomerization of NLRC4 and that NAIP2/NLRC4 physically associates with PrgJ but not flagellin, whereas NAIP5/NLRC4 associates with flagellin but not PrgJ. Taken together, our results identify NAIPs as immune sensor proteins and provide biochemical evidence for a simple receptor-ligand model for activation of the NAIP/NLRC4 inflammasomes.
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