Regulation of Innate Immunity by Pyrin Proteins

摘要 TLR和NLR家族成员的细胞外和细胞内病原体识别启动先天 免疫和炎症反应。TLRs和NLRs都激活了NF-kB和MAPK信号通路 导致多种炎性细胞因子(如肿瘤坏死因子、白介素6和白介素8)的转录和分泌。不像 TLRs，NLRs还可以激活多蛋白炎症体复合体，使proIL-1和proIL-18处理为 它们的活跃形式。在不到五年的时间里，NLRs与遗传性自体炎症性疾病和 对越来越多的病原体的先天免疫反应，包括炭疽杆菌、鼠疫耶尔森菌、 和图拉氏方济氏菌。含有NLR蛋白的比林相互作用导致炎性小体组装 与ASC(带有卡片的凋亡斑点蛋白)一起募集和激活Caspase-1。这个 炎性小体复合体也可能参与诱导一种形式的caspase-1依赖的细胞凋亡。ASC 与NLRs和蛋白质派林的相互作用也可以激活核因子-kB。最近，只有吡喃的发现 同时影响核因子-kB和炎症体功能的蛋白质(POP)为宿主提供了一条途径 对促炎反应及其病原体颠覆的调节。这样做的长期目标是 建议理解仅依赖于吡喃的先天免疫反应的分子调控。 蛋白质。此外，对炎症体调节的理解将扩展到宿主与病原体的相互作用。 炎症小体功能或颠覆被证明是免疫或疾病的关键。 具体地说，我们已经确定了第二个人类POP(POP2)，它抑制NF-kB p65的活性，与 ASC，并阻止一些NLR激活的炎性小体的激活。我们将检验这一假设 POP2通过干扰炎症体-2来负向调节促炎反应。 介导caspase-1激活和减弱核因子-kB信号，从而抑制有害的炎症 以及防止或减少先天性免疫反应中巨噬细胞的死亡。组合体宽广 基于分子和体内的方法，我们将解决以下目标：1)建立分子基础 针对POP2对核因子-kB的抑制2)建立POP2调节炎症体的分子基础 激活。3)确定POP2在体内调节炎性先天免疫反应中的作用。

SUMMARY Extracellular and intracellular pathogen recognition by members of the TLR and NLR families initiate innate immune and inflammatory responses. TLRs and NLRs both activate the NF-kB and MAPK signaling pathways leading to the transcription and secretion of multiple inflammatory cytokines (e.g. TNF¿, IL-6, and IL-8). Unlike TLRs, NLRs can also activate multiprotein inflammasome complexes that processes proIL-1¿ and proIL-18 to their active forms. In less than five years, NLRs have been linked to hereditary autoinflammatory diseases and innate immune response towards a growing number of pathogens, including Bacillus anthracis, Yersinia pestis, and Francisella tularensis. Inflammasome assembly results from interaction of a pyrin containing NLR protein with ASC (apoptotic speck protein with a CARD) followed by recruitment and activation of Caspase-1. The inflammasome complex may also be involved in inducing a form of caspase-1 dependent apoptosis. ASC interactions with NLRs and the protein Pyrin can also activate NF-kB. Recently, the discovery of pyrin only proteins (POPs) that influence both NF-kB and inflammasome functions has suggested an avenue for host regulation of the proinflammatory response and pathogen subversion thereof. The long-term objective of this proposal is to understand the molecular regulation of innate immune responses dependent upon pyrin only proteins. Further, understanding of inflammasome regulation will be extended to host-pathogen interactions where inflammasome function or subversion is demonstrated to be critical for immunity or disease. Specifically, we have identified a second human POP (POP2) which inhibits NF-kB p65 activity, interacts with ASC, and prevents the activation of a number of NLR activated inflammasomes. We will test the hypothesis that POP2 negatively regulates proinflammatory responses by interfering with both inflammasome- mediated caspase-1 activation and attenuating NF-kB signals, thus dampening harmful inflammation and preventing or reducing macrophage death during innate immune responses. Combining broad based molecular and in vivo approaches, we will address the following aims: 1) Establish the molecular basis for NF-kB inhibition by POP2 2) Establish the molecular basis for POP2 regulation of inflammasome activation. 3) Establish the in vivo role of POP2 in modulating inflammatory innate immune responses.