近日，国际著名杂志PLoS Pathogen在线刊登了加拿大多伦多大学研究者的最新研究成果“Proteolytic Processing of Nlrp1b Is Required for inflammasome Activity ”，文章中，研究者揭示Nlrp1b的蛋白酶解加工需要炎性小体的活化。
炎性小体（Inflammasomes）是一种多重的蛋白质复合物，可以推进前细胞凋亡蛋白酶对于病原体相关的分子模式（PAMPS）或内源性危险相关的分子模式（DAMPS）产生必要的应答。
Nlrp1b是一种NOD样受体，可以检测炭疽致死毒素的催化活性，随后通过共寡聚体化来激活前细胞凋亡蛋白酶-1的活化。
人类的Nlrp1b具有NACHT结构域并且具有发现能够自我组装的结构域FIIND的功能。Nlrp1b存在5个等位基因，而且可以间接感应炭疽致死毒素的催化活性。
这项研究中，研究者Jeremy Mogridge研究者Nlrp1b识别的FIIND功能，研究者使用了一系列的平截突变来识别FIIND的最小区域，以便引导CARD结构域的寡聚化和前细胞凋亡蛋白酶的活化。Nlrp1b片段的丙氨酸替代突变体可以损伤自我组合以及前细胞凋亡蛋白酶-1的活化。相同的突变也可以导致全长Nlrp1b的功能缺失，因此研究者假设Nlrp1b的分裂对其功能的发挥至关重要。Nlrp1b1和Nlrp1b3的序列的比较使我们识别出了单一的氨基酸，这样就决定了其在分裂的易感性上的不同。研究者表示，通过引入一个异源性的TEV蛋白酶位点到Nlrp1b1的分裂缺失的突变体中对于维持其活性必不可少，这样也可以揭示激活需要TEV蛋白酶的共同表达。最终，研究者表示Nlrp1b1的分裂并不会使其自身自我组合，而是增强了前细胞凋亡蛋白酶-1的募集反应。（生物谷Bioon.com）
doi:10.1371/journal.ppat.1002659
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Proteolytic Processing of Nlrp1b Is Required for Inflammasome Activity
Bradley C. Frew, Vineet R. Joag, Jeremy Mogridge*
Nlrp1b is a NOD-like receptor that detects the catalytic activity of anthrax lethal toxin and subsequently co-oligomerizes into a pro-caspase-1 activation platform known as an inflammasome. Nlrp1b has two domains that promote oligomerization: a NACHT domain, which is a member of the AAA+ ATPase family, and a poorly characterized Function to Find Domain (FIIND). Here we demonstrate that proteolytic processing within the FIIND generates N-terminal and C-terminal cleavage products of Nlrp1b that remain associated in both the auto-inhibited state and in the activated state after cells have been treated with lethal toxin. Functional significance of cleavage was suggested by the finding that mutations that block processing of Nlrp1b also prevent the ability of Nlrp1b to activate pro-caspase-1. By using an uncleaved mutant of Nlrp1b, we established the importance of cleavage by inserting a heterologous TEV protease site into the FIIND and demonstrating that TEV protease processed this site and induced inflammasome activity. Proteolysis of Nlrp1b was shown to be required for the assembly of a functional inflammasome: a mutation within the FIIND that abolished cleavage had no effect on self-association of a FIIND-CARD fragment, but did reduce the recruitment of pro-caspase-1. Our work indicates that a post-translational modification enables Nlrp1b to function.
