The introduction of RNA-DNA differences underlies interindividual variation in the human IL12RB1 mRNA repertoire.

Abstract:

: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.

authors

Turner AJ,Aggarwal P,Miller HE,Waukau J,Routes JM,Broeckel U,Robinson RT

doi

10.1073/pnas.1515978112

subject

Has Abstract

pub_date

2015-12-15 00:00:00

pages

15414-9

issue

50

eissn

0027-8424

issn

1091-6490

pii

1515978112

journal_volume

112

pub_type

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