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Nat Commun. 2019 Jul 19;10(1):3238. doi: 10.1038/s41467-019-11076-1.

Alternative splicing regulates stochastic NLRP3 activity.

Author information

1
Institute of Innate Immunity, University Hospital, University of Bonn, 53127, Bonn, Germany.
2
University of California, San Diego School of Medicine, La Jolla, CA, 92093, USA.
3
Gene Center, Ludwig-Maximilians-Universität München, 81377, Munich, Germany.
4
Institute of Structural Biology, University Hospital, University of Bonn, 53127, Bonn, Germany.
5
Medical Faculty, Institute of Cellular Neurosciences, University of Bonn, 53127, Bonn, Germany.
6
Ludwig Institute of Cancer Research, San Diego branch, La Jolla, CA, 92093, USA.
7
University of California, San Diego School of Medicine, La Jolla, CA, 92093, USA. hahoffman@ucsd.edu.
8
Institute of Innate Immunity, University Hospital, University of Bonn, 53127, Bonn, Germany. eicke.latz@uni-bonn.de.
9
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, 01655, USA. eicke.latz@uni-bonn.de.
10
German Center for Neurodegenerative Diseases, 53127, Bonn, Germany. eicke.latz@uni-bonn.de.

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.

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