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Alternative splicing regulates stochastic NLRP3 activity

dc.contributor.authorHoss, Florian
dc.contributor.authorMueller, James L.
dc.contributor.authorRojas Ringeling, Francisca
dc.contributor.authorRodriguez-Alcazar, Juan F.
dc.contributor.authorBrinkschulte, Rebecca
dc.contributor.authorSeifert, Gerald
dc.contributor.authorStahl, Rainer
dc.contributor.authorBroderick, Lori
dc.contributor.authorPutnam, Chris D.
dc.contributor.authorKolodner, Richard D.
dc.contributor.authorCanzar, Stefan
dc.contributor.authorGeyer, Matthias
dc.contributor.authorHoffman, Hal M.
dc.contributor.authorLatz, Eicke
dc.date2022-08-11T08:09:53.000
dc.date.accessioned2022-08-23T16:47:44Z
dc.date.available2022-08-23T16:47:44Z
dc.date.issued2019-07-19
dc.date.submitted2019-08-09
dc.identifier.citation<p>Nat Commun. 2019 Jul 19;10(1):3238. doi: 10.1038/s41467-019-11076-1. <a href="https://doi.org/10.1038/s41467-019-11076-1">Link to article on publisher's site</a></p>
dc.identifier.issn2041-1723 (Linking)
dc.identifier.doi10.1038/s41467-019-11076-1
dc.identifier.pmid31324763
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41139
dc.description.abstractLeucine-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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=31324763&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectInflammasome
dc.subjectInnate immunity
dc.subjectNOD-like receptors
dc.subjectRNA splicing
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemical Phenomena, Metabolism, and Nutrition
dc.subjectGenetic Phenomena
dc.subjectHemic and Immune Systems
dc.subjectImmunity
dc.subjectNucleic Acids, Nucleotides, and Nucleosides
dc.titleAlternative splicing regulates stochastic NLRP3 activity
dc.typeJournal Article
dc.source.journaltitleNature communications
dc.source.volume10
dc.source.issue1
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=4945&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/3929
dc.identifier.contextkey15087850
refterms.dateFOA2022-08-23T16:47:44Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathoapubs/3929
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.source.pages3238


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Copyright © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Except where otherwise noted, this item's license is described as Copyright © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.