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

doi:10.1038/s41467-019-11076-1

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

Computer Science and Engineering

Research output: Contribution to journal › Article › peer-review

43 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 language	English (US)
Article number	3238
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11076-1
State	Published - 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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title = "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.",

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

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AU - Hoss, Florian

AU - Mueller, James L.

AU - Rojas Ringeling, Francisca

AU - Rodriguez-Alcazar, Juan F.

AU - Brinkschulte, Rebecca

AU - Seifert, Gerald

AU - Stahl, Rainer

AU - Broderick, Lori

AU - Putnam, Chris D.

AU - Kolodner, Richard D.

AU - Canzar, Stefan

AU - Geyer, Matthias

AU - Hoffman, Hal M.

AU - Latz, Eicke

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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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Alternative splicing regulates stochastic NLRP3 activity

Abstract

All Science Journal Classification (ASJC) codes

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