近日,，國際著名雜志PLoS Pathogen在線刊登了加拿大多倫多大學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體的活化,。

炎性小體（Inflammasomes）是一種多重的蛋白質復合物，可以推進前細胞凋亡蛋白酶對于病原體相關的分子模式（PAMPS）或內源性危險相關的分子模式（DAMPS）產生必要的應答,。

Nlrp1b是一種NOD樣受體,，可以檢測炭疽致死毒素的催化活性，隨后通過共寡聚體化來激活前細胞凋亡蛋白酶-1的活化,。

人類的Nlrp1b具有NACHT結構域并且具有發(fā)現能夠自我組裝的結構域FIIND的功能,。Nlrp1b存在5個等位基因，而且可以間接感應炭疽致死毒素的催化活性,。

這項研究中,，研究者Jeremy Mogridge研究者Nlrp1b識別的FIIND功能，研究者使用了一系列的平截突變來識別FIIND的最小區(qū)域,，以便引導CARD結構域的寡聚化和前細胞凋亡蛋白酶的活化,。Nlrp1b片段的丙氨酸替代突變體可以損傷自我組合以及前細胞凋亡蛋白酶-1的活化。相同的突變也可以導致全長Nlrp1b的功能缺失，因此研究者假設Nlrp1b的分裂對其功能的發(fā)揮至關重要,。Nlrp1b1和Nlrp1b3的序列的比較使我們識別出了單一的氨基酸,，這樣就決定了其在分裂的易感性上的不同。研究者表示,，通過引入一個異源性的TEV蛋白酶位點到Nlrp1b1的分裂缺失的突變體中對于維持其活性必不可少,，這樣也可以揭示激活需要TEV蛋白酶的共同表達。最終,，研究者表示Nlrp1b1的分裂并不會使其自身自我組合,，而是增強了前細胞凋亡蛋白酶-1的募集反應。（生物谷Bioon.com）

doi:10.1371/journal.ppat.1002659
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PMID:
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.