The introduction of RNA-DNA differences underlies interindividual variation in the human IL12RB1 mRNA repertoire. Proc Natl Acad Sci U S A 2015 Dec 15;112(50):15414-9
Date
12/02/2015Pubmed ID
26621740Pubmed Central ID
PMC4687591DOI
10.1073/pnas.1515978112Scopus ID
2-s2.0-84950107978 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
Human interleukin 12 and interleukin 23 (IL12/23) influence susceptibility or resistance to multiple diseases. However, the reasons underlying individual differences in IL12/23 sensitivity remain poorly understood. Here we report that in human peripheral blood mononuclear cells (PBMCs) and inflamed lungs, the majority of interleukin-12 receptor β1 (IL12RB1) mRNAs contain a number of RNA-DNA differences (RDDs) that concentrate in sequences essential to IL12Rβ1's binding of IL12p40, the protein subunit common to both IL-12 and IL-23. IL12RB1 RDDs comprise multiple RDD types and are detectable by next-generation sequencing and classic Sanger sequencing. As a consequence of these RDDs, the resulting IL12Rβ1 proteins have an altered amino acid sequence that could not be predicted on the basis of genomic DNA sequencing alone. Importantly, the introduction of RDDs into IL12RB1 mRNAs negatively regulates IL12Rβ1's binding of IL12p40 and is sensitive to activation. Collectively, these results suggest that the introduction of RDDs into an individual's IL12RB1 mRNA repertoire is a novel determinant of IL12/23 sensitivity.
Author List
Turner AJ, Aggarwal P, Miller HE, Waukau J, Routes JM, Broeckel U, Robinson RTAuthors
Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of WisconsinAmy Turner Research Scientist I in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultBase Sequence
DNA
Gene Expression Regulation
Humans
Interleukin-12
Lung
Models, Biological
Molecular Sequence Data
Phytohemagglutinins
Pneumonia
Protein Binding
RNA
RNA, Messenger
Receptors, Interleukin-12
Recombinant Proteins