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Alternative splicing regulates stochastic NLRP3 activity

Author

Listed:
  • 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
    Ludwig Institute of Cancer Research, San Diego branch)

  • Richard D. Kolodner

    (University of California, San Diego School of Medicine
    Ludwig Institute of Cancer Research, San Diego branch)

  • 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
    Division of Infectious Diseases and Immunology, University of Massachusetts Medical School
    German Center for Neurodegenerative Diseases)

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.

Suggested Citation

  • 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 , 2019. "Alternative splicing regulates stochastic NLRP3 activity," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11076-1
    DOI: 10.1038/s41467-019-11076-1
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