Alternative splicing regulates stochastic NLRP3 activity.,Nature Communications

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Alternative splicing regulates stochastic NLRP3 activity.
Nature Communications ( IF 14.7 ) Pub Date : 2019-07-19 , DOI: 10.1038/s41467-019-11076-1
Florian Hoss ₁ , James L Mueller ₂ , Francisca Rojas Ringeling ₃ , Juan F Rodriguez-Alcazar ₁ , Rebecca Brinkschulte ₄ , Gerald Seifert ₅ , Rainer Stahl ₁ , Lori Broderick ₂ , Chris D Putnam _{2,

6} , Richard D Kolodner _{2,

6} , Stefan Canzar ₃ , Matthias Geyer ₄ , Hal M Hoffman ₂ , Eicke Latz _{1,

7,

8}

Affiliation

Leucine-rich repeat (LRR) domains are evolutionarily conserved in proteins that function in development and immunity. Here we report strict exonic modularity of LRR domains of several human gene families, which is a precondition for alternative splicing (AS). We provide evidence for AS of LRR domain within several Nod-like receptors, most prominently the inflammasome sensor NLRP3. Human NLRP3, but not mouse NLRP3, is expressed as two major isoforms, the full-length variant and a variant lacking exon 5. Moreover, NLRP3 AS is stochastically regulated, with NLRP3 ∆ exon 5 lacking the interaction surface for NEK7 and hence loss of activity. Our data thus reveals unexpected regulatory roles of AS through differential utilization of LRRs modules in vertebrate innate immunity.

中文翻译：

替代剪接调节随机的NLRP3活性。

富含亮氨酸的重复（LRR）域在具有发育和免疫功能的蛋白质中在进化上是保守的。在这里，我们报告了几个人类基因家族的LRR域的严格外显模块性，这是替代剪接（AS）的前提。我们提供了几种Nod样受体内LRR结构域的AS的证据，其中最明显的是炎性体传感器NLRP3。人NLRP3而非小鼠NLRP3被表达为两种主要的同工型，全长变异体和缺乏外显子5的变异体。此外，NLRP3 AS受随机调控，NLRP3 ∆外显子5缺乏NEK7的相互作用表面，因此丧失了活动。因此，我们的数据揭示了通过在脊椎动物先天免疫中不同程度地利用LRRs模块来发挥AS的意想不到的调节作用。

更新日期：2019-07-19

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