IL-17 Attenuates Degradation of ARE-mRNAs by Changing the Cooperation between AU-Binding Proteins and microRNA16

Saheli Chowdhury, Annemiek Dijkhuis, Sabrina Steiert and René Lutter

PLOS Genetics, 2013, vol. 9, issue 9, 1-13

Abstract: Interleukin 17A (IL-17), a mediator implicated in chronic and severe inflammatory diseases, enhances the production of pro-inflammatory mediators by attenuating decay of the encoding mRNAs. The decay of many of these mRNAs depends on proteins (AUBps) that target AU-rich elements in the 3′-untranslated region of mRNAs and facilitate either mRNA decay or stabilization. Here we show that AUBps and the target mRNA assemble in a novel ribonucleoprotein complex in the presence of microRNA16 (miR16), which leads to the degradation of the target mRNA. Notably, IL-17 attenuates miR16 expression and promotes the binding of stabilizing AUBps over that of destabilizing AUBps, reducing mRNA decay. These findings indicate that miR16 independently of a seed sequence, directs the competition between degrading and stabilizing AUBps for target mRNAs. Since AUBps affect expression of about 8% of the human transcriptome and miR16 is ubiquitously expressed, IL-17 may in addition to inflammation affect many other cellular processes.Author Summary: Inflammation is driven by inflammatory mediators. Interleukin 17A (IL-17) is implicated in chronic and severe inflammation and exaggerates production of inflammatory mediators. This is due, at least in part, to the IL-17-attenuated degradation of mRNAs encoding these inflammatory mediators, but the underlying mechanism has remained elusive. Most of these mRNAs contain AU-rich elements in their 3′-untranslated region and are targeted by AU-binding proteins (AUBps) that promote either mRNA degradation or stabilization. Here we show that IL-17 directs the AU-mediated mRNA degradation (AMD pathway) by modulating the interaction of degrading and stabilizing AUBps via microRNA16 (miR16). Whereas microRNAs target mRNAs to the RISC pathway for degradation by binding to a seed sequence, miR16 drives degradation by the AMD pathway without an apparent seed sequence. Transcriptome analyses have revealed that the expression of 8% of all eukaryotic transcripts is dependent on the AMD pathway. Therefore, the impact of IL-17 on inflammatory diseases may extend beyond the production of inflammatory mediators to processes like tissue repair, cell cycle, etc. In addition, targeting AUBp and/or miR16 may provide a novel therapeutic option to combat the IL-17 axis of inflammation.

Date: 2013
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003747 (text/html)
https://journals.plos.org/plosgenetics/article/fil ... 03747&type=printable (application/pdf)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:plo:pgen00:1003747

DOI: 10.1371/journal.pgen.1003747

Access Statistics for this article

More articles in PLOS Genetics from Public Library of Science
Bibliographic data for series maintained by plosgenetics ().