Alternative splicing regulates stochastic NLRP3 activity

Florian Hoss, James L. Mueller, Francisca Rojas Ringeling, Juan F. Rodriguez-Alcazar, Rebecca Brinkschulte, Gerald Seifert, Rainer Stahl, Lori Broderick, Chris D. Putnam, Richard D. Kolodner, Stefan Canzar, Matthias Geyer, Hal M. Hoffman, Eicke Latz

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageEnglish (US)
Article number3238
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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