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 () and Eicke Latz ()
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Florian Hoss: University Hospital, University of Bonn
James L. Mueller: University of California, San Diego School of Medicine
Francisca Rojas Ringeling: Gene Center, Ludwig-Maximilians-Universität München
Juan F. Rodriguez-Alcazar: University Hospital, University of Bonn
Rebecca Brinkschulte: University Hospital, University of Bonn
Gerald Seifert: Medical Faculty, Institute of Cellular Neurosciences, University of Bonn
Rainer Stahl: University Hospital, University of Bonn
Lori Broderick: University of California, San Diego School of Medicine
Chris D. Putnam: University of California, San Diego School of Medicine
Richard D. Kolodner: University of California, San Diego School of Medicine
Stefan Canzar: Gene Center, Ludwig-Maximilians-Universität München
Matthias Geyer: University Hospital, University of Bonn
Hal M. Hoffman: University of California, San Diego School of Medicine
Eicke Latz: University Hospital, University of Bonn

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11076-1

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