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Alternative splicing regulates stochastic NLRP3 activity.

ABSTRACT: 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.

SUBMITTER: Hoss F

PROVIDER: S-EPMC6642158 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Alternative splicing regulates stochastic NLRP3 activity.

Hoss Florian F Mueller James L JL Rojas Ringeling Francisca F Rodriguez-Alcazar Juan F JF Brinkschulte Rebecca R Seifert Gerald G Stahl Rainer R Broderick Lori L Putnam Chris D CD Kolodner Richard D RD Canzar Stefan S Geyer Matthias M Hoffman Hal M HM Latz Eicke E

Nature communications 20190719 1

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 ...[more]

PMID: 31324763

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