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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing*
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Amino Acid Sequence
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Animals
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Cells, Cultured
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Exons / genetics*
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HEK293 Cells
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Humans
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Immunity, Innate / genetics
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Inflammasomes / chemistry
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Inflammasomes / genetics*
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Inflammasomes / metabolism
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Macrophages / metabolism
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NIMA-Related Kinases / genetics
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NIMA-Related Kinases / metabolism
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NLR Family, Pyrin Domain-Containing 3 Protein / chemistry
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NLR Family, Pyrin Domain-Containing 3 Protein / genetics*
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NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
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Neoplasm Proteins / chemistry
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Protein Domains
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Protein Isoforms / chemistry
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Stochastic Processes
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Swine
Substances
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Inflammasomes
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LRPPRC protein, human
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NLR Family, Pyrin Domain-Containing 3 Protein
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NLRP3 protein, human
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Neoplasm Proteins
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Protein Isoforms
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NEK7 protein, human
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NIMA-Related Kinases